Non-sedating dexmedetomidine treatment regimens

ABSTRACT

Disclosed herein are methods of administering relatively high doses of dexmedetomidine or a pharmaceutically acceptable salt thereof to a human subject, without also inducing significant sedation. The disclosed methods are particularly suitable for the treatment of agitation, especially when associated with neurodegenerative and/or neuropsychiatric diseases such as schizophrenia, bipolar illness such as bipolar disorder or mania, dementia, depression, or delirium.

FIELD

Disclosed herein are methods of treating a human subject having a condition (e.g., agitation) which can be improved using an alpha-2 adrenergic receptor agonist. The methods comprise administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a suitable dose, and via an appropriate route of administration, to achieve a plasma concentration profile that provides a rapid improvement to the subject's condition without also inducing significant sedation. The administration regimens are also selected to provide maximum therapeutic benefit to the subject, without incurring any significant side effects, such as undesirable cardiovascular events. The disclosed methods are particularly suitable for the treatment of agitation or signs of agitation, especially when associated with schizophrenia or a bipolar illness, such as bipolar I disorder or bipolar II disorder.

BACKGROUND

On Dec. 17, 1999, the U.S. Food and Drug Administration approved a dexmedetomidine product, PRECEDEX®, formulated as an intravenous solution for continuous infusion, and indicated as a sedative agent for initially intubated and mechanically ventilated patients during treatment in an intensive care setting. PRECEDEX® was later approved as a sedative agent for non-intubated patients prior to and/or during surgical and other procedures.

Dexmedetomidine has also been administered intravenously and via other routes to treat a range of conditions, often peri- or post-surgery, including the treatment of pain, anxiety, delirium, withdrawal symptoms, sleep disorders and agitation. However, administration of dexmedetomidine in an appropriate dosage form to provide effective, rapid, relief for the subject without also causing significant sedation is a challenging task. The utilization of dexmedetomidine has also been limited in clinical practice due to its common side effects, such as hypotension and bradycardia. For example, significant cardiovascular side-effects have occurred at therapeutic doses following administration of dexmedetomidine hydrochloride via a sublingual spray or tablets, or intravenously. Thus, a continuing, unmet need exists for an effective dexmedetomidine product which does not cause significant sedation, and desirably is effective without also producing significant adverse effects, such as cardiovascular events. The unmet need is particularly acute for non-addictive medicines that can effectively treat agitation or signs of agitation without also producing the aforementioned adverse effects and sedation.

SUMMARY

The present disclosure is related to the discovery that an agitated human subject with schizophrenia or bipolar I or II disorder and a hepatic impairment can be treated with an oromucosal formulation comprising dexmedetomidine or a pharmaceutically acceptable salt thereof in a lower dose than a similar human subject without a hepatic impairment.

The present disclosure provides a method of using dexmedetomidine, comprising:

-   -   administering an initial dose of dexmedetomidine or a         pharmaceutically acceptable salt thereof in an oromucosal         formulation to a human subject having an agitation associated         with schizophrenia or bipolar I or II disorder;     -   optionally administering a second dose of dexmedetomidine or the         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject at least two hours after and         within 24 hours of the initial dose; and optionally         administering a third dose of dexmedetomidine or the         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject at least two hours after the         second dose and within 24 hours of the initial dose;     -   wherein the administration of the dexmedetomidine does not         exceed a maximum total daily dosage;     -   wherein the human subject has a hepatic impairment;     -   wherein the second dose and the third dose are 60 mcg of         dexmedetomidine each;     -   wherein the initial dose is 90 mcg of dexmedetomidine and the         maximum total daily dosage is 210 mcg of dexmedetomidine if the         agitation is mild or moderate and if the hepatic impairment is         mild or moderate;     -   wherein the initial dose is 120 mcg of dexmedetomidine and the         maximum total daily dosage is 240 mcg of dexmedetomidine if the         agitation is severe and if the hepatic impairment is mild or         moderate;     -   wherein the initial dose is 60 mcg of dexmedetomidine and the         maximum total daily dosage is 180 mcg of dexmedetomidine if the         agitation is mild or moderate and if the hepatic impairment is         severe; and     -   wherein the initial dose is 90 mcg of dexmedetomidine and the         maximum total daily dosage is 210 mcg of dexmedetomidine if the         agitation is severe and if the hepatic impairment is severe.

In some embodiments of the method, the second dose of dexmedetomidine is optional, and in some other embodiments of the methods the second dose of dexmedetomidine is not optional.

In some embodiments of the method, the third dose of dexmedetomidine is optional and in some other embodiments of the methods the third dose of dexmedetomidine is not optional.

In some embodiments of the method, agitation that is mild or moderate is defined as a Positive and Negative Syndrome Scale-Excited Component (PEC) score of 19 or lower. In some embodiments of the method, agitation that is mild is defined as a PEC score of 13 or lower. In some embodiments of the method, agitation that is moderate is defined as a PEC score of 14 to 19 inclusive. In some embodiments of the method, agitation that is severe is defined as a PEC score of 20 or higher.

In some embodiments of the method, the hepatic impairment is mild that is defined as Child-Pugh Class A. In some embodiments of the method, the hepatic impairment is moderate that is defined as Child-Pugh Class B. In some embodiments of the method, the hepatic impairment is severe that is defined as Child-Pugh Class C.

In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In some embodiments of the method, the agitation is mild or moderate and the hepatic impairment is mild or moderate, and wherein the initial dose is 90 mcg of dexmedetomidine and the maximum total daily dosage is 210 mcg of dexmedetomidine. In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In some embodiments of the method, the agitation is severe and the hepatic impairment is mild or moderate, and wherein the initial dose is 120 mcg of dexmedetomidine and the maximum total daily dosage is 240 mcg of dexmedetomidine. In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In some embodiments of the method, the agitation is mild or moderate and the hepatic impairment is severe, and wherein the initial dose is 60 mcg of dexmedetomidine and the maximum total daily dosage is 180 mcg of dexmedetomidine. In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In some embodiments of the method, the agitation is severe and the hepatic impairment is severe, and wherein the initial dose is 90 mcg of dexmedetomidine and the maximum total daily dosage is 210 mcg of dexmedetomidine. In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

A method of using an oromucosal formulation of dexmedetomidine for an acute treatment of an agitation associated with schizophrenia or bipolar I or II disorder in a human subject, wherein the human subject does not have a hepatic impairment, the method comprising:

-   -   administering an initial dose of dexmedetomidine or a         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject;     -   optionally administering a second dose of dexmedetomidine or the         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject at least two hours after and         within 24 hours of the initial dose; and     -   optionally administering a third dose of dexmedetomidine or the         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject at least two hours after the         second dose and within 24 hours of the initial dose;     -   wherein the administration of the dexmedetomidine does not         exceed a maximum total daily dosage;     -   wherein the initial dose, the second dose, the third dose, and         the maximum total daily dosage are 120 mcg, 60 mcg, 60 mcg, and         240 mcg of dexmedetomidine, respectively, if the human subject         is younger than 65 years of age and if the agitation is mild or         moderate;     -   wherein the initial dose, the second dose, the third dose, and         the maximum total daily dosage are 180 mcg, 90 mcg, 90 mcg, and         360 mcg of dexmedetomidine, respectively, if the human subject         is younger than 65 years of age and if the agitation is severe;         and     -   wherein the initial dose, the second dose, the third dose, and         the maximum total daily dosage are 120 mcg, 60 mcg, 60 mcg, and         240 mcg of dexmedetomidine, respectively, if the human subject         is 65 years of age or older and if the agitation is mild,         moderate, or severe.

A method of using an oromucosal formulation of dexmedetomidine for an acute treatment of an agitation associated with schizophrenia or bipolar I or II disorder in a human subject, the method comprising:

-   -   administering an initial dose of dexmedetomidine or a         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject;     -   optionally administering a second dose of dexmedetomidine or the         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject at least two hours after and         within 24 hours of the initial dose; and     -   optionally administering a third dose of dexmedetomidine or the         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject at least two hours after the         second dose and within 24 hours of the initial dose;     -   wherein the administration of the dexmedetomidine does not         exceed a maximum total daily dosage;     -   wherein the initial dose, the second dose, the third dose, and         the maximum total daily dosage are 120 mcg, 60 mcg, 60 mcg, and         240 mcg of dexmedetomidine, respectively, if the human subject         is younger than 65 years of age and if the agitation is mild or         moderate;     -   wherein the initial dose, the second dose, the third dose, and         the maximum total daily dosage are 180 mcg, 90 mcg, 90 mcg, and         360 mcg of dexmedetomidine, respectively, if the human subject         is younger than 65 years of age and if the agitation is severe;         and     -   wherein the initial dose, the second dose, the third dose, and         the maximum total daily dosage are 120 mcg, 60 mcg, 60 mcg, and         240 mcg of dexmedetomidine, respectively, if the human subject         is 65 years of age or older and if the agitation is mild,         moderate, or severe.

In any embodiments of the method, the oromucosal formulation further comprises at least one water-soluble polymer. In some embodiments, the at least one water-soluble polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxy methylcellulose, methylcellulose, polyethylene oxide (PEO), and mixtures thereof. In some embodiments, the at least one water-soluble polymer is hydroxypropyl cellulose.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the mean change from baseline in PEC total score in schizophrenic patients (Intent to treat Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg and 180 μg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 2 depicts the percent of responders in PEC total score over time in schizophrenic patients (Intent to treat Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg and 180 μg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 3 depicts resolution of agitation as measured by achieving an ACES Score of at least 4 over time in schizophrenic patients (Intent to treat Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg and 180 μg) versus a placebo group. The error bars in the figure represent “standard error.” The preparation of dexmedetomidine hydrochloride sublingual films (60 μg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 4 depicts percent of responders in CGI-I Score over time in schizophrenic patients (Intent to treat Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg and 180 μg) versus a placebo group. The error bars in the figure represent “standard error.” The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 5A depicts the mean dexmedetomidine plasma concentration vs. nominal time sorted by dose and redose (Semilog Scale) in schizophrenic patients (Pharmacokinetic Population) treated with a sublingual film containing dexmedetomidine hydrochloride (20 μg, 20 μg (redose), 60 μg, 80 μg, 120 μg and 180 μg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual films (20 μg and 60 μg) are exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 5B depicts the mean dexmedetomidine plasma concentration vs. nominal time sorted by dose and redose (Linear Scale) in schizophrenic patients (Pharmacokinetic Population) treated with a sublingual film containing dexmedetomidine hydrochloride (20 μg, 20 μg (redose), 60 μg, 80 μg, 120 μg and 180 μg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual films (20 μg and 60 μg) are exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 6A depicts the mean values for resting systolic blood pressure (SBP) over time in schizophrenic patients (Safety Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg and 180 μg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 6B depicts the mean values for resting diastolic blood pressure (DBP) over time in schizophrenic patients (Safety Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg and 180 μg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 6C depicts the mean values for resting heart rate (HR) over time in schizophrenic patients (Safety Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg and 180 μg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 7A depicts the mean change from baseline for resting systolic blood pressure (SBP) over time in schizophrenic patients (Safety Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg and 180 μg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 7B depicts the mean change from baseline for resting diastolic blood pressure (DBP) over time in schizophrenic patients (Safety Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg and 180 μg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 7C depicts the mean change from baseline for resting heart rate (HR) over time in schizophrenic patients (Safety Population) treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg and 180 μg) versus a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is exemplified in Example 1 and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg and 180 μg) are exemplified in Example 2.

FIG. 8 shows the mean dexmedetomidine plasma log concentration vs. time for dose levels 10 μg, 20 μg and 40 μg of dexmedetomidine sublingual film (Semi-log scale). Error bars represent 1 standard deviation.

FIG. 9A depicts individual dexmedetomidine concentration-time profiles for all subjects by dose after administration of dexmedetomidine sublingual film (10 μg) Semi-log Scale. Dexmedetomidine sublingual film is exemplified in Example 1.

FIG. 9B depicts individual dexmedetomidine concentration-time profiles for all subjects by dose after administration of dexmedetomidine sublingual film (20 μg) Semi-log Scale. Dexmedetomidine sublingual film is exemplified in Example 1.

FIG. 9C depicts individual dexmedetomidine concentration-time profiles for all subjects by dose after administration of dexmedetomidine sublingual film (40 μg) Semi-log Scale. The preparation of Dexmedetomidine sublingual film is exemplified in Example 1.

FIG. 10 depicts the mean VAS/S score vs. nominal time after administration of dexmedetomidine sublingual film (10 μg, 20 μg, 40 μg) and placebo. Dexmedetomidine sublingual film (10 μg and 20 μg) and the preparation of dexmedetomidine sublingual film (40 μg) are exemplified in Example 1.

FIG. 11 depicts standing systolic BP vs nominal time after administration of dexmedetomidine sublingual film (10 μg, 20 μg, 40 μg) and placebo. Dexmedetomidine sublingual film (10 μg and 20 μg) and the preparation of dexmedetomidine sublingual film (40 μg) are exemplified in Example 1.

FIG. 12 depicts supine systolic BP. vs nominal time after administration of dexmedetomidine sublingual film 10 μg, 20 μg and 40 μg and placebo. Dexmedetomidine sublingual film (10 μg and 20 μg) and the preparation of dexmedetomidine sublingual film (40 μg) are exemplified in Example 1.

FIG. 13 depicts standing diastolic BP vs nominal time after administration of dexmedetomidine sublingual film 10 μg, 20 μg and 40 μg and placebo. Dexmedetomidine sublingual film (10 μg and 20 μg) and the preparation of dexmedetomidine sublingual film (40 μg) are exemplified in Example 1.

FIG. 14 depicts supine diastolic BP vs nominal time after administration of dexmedetomidine sublingual film 10 μg, 20 μg and 40 μg and placebo. Dexmedetomidine sublingual film (10 μg and 20 μg) and the preparation of dexmedetomidine sublingual film (40 μg) are exemplified in Example 1.

FIG. 15 depicts pulse rate vs nominal time after administration of dexmedetomidine sublingual film 10 μg, 20 μg and 40 μg and placebo. Dexmedetomidine sublingual film (10 and 20 μg) and the preparation of dexmedetomidine sublingual film (40 μg) are exemplified in Example 1.

FIG. 16 depicts the percentage of schizophrenic patients achieving RASS −1 in the treatment arm (IV dexmedetomidine hydrochloride treated group) versus placebo group.

FIG. 17 depicts the mean drop in PEC score with time in schizophrenic patients in the treatment arm (IV dexmedetomidine hydrochloride treated group) versus placebo group.

FIG. 18 depicts the maximum doses of IV dexmedetomidine hydrochloride received by schizophrenic patients for the treatment of agitation.

FIG. 19 depicts the total intravenous dose of dexmedetomidine hydrochloride received by schizophrenic patients for the treatment of agitation.

FIG. 20 depicts the mean plasma concentration (pg/ml) vs actual time in schizophrenic patients treated with dexmedetomidine hydrochloride.

FIG. 21A depicts the change in PEC score from baseline in schizophrenia patients until 2 hours post-dose of 120 μg and 180 μg dexmedetomidine sublingual thin film (as exemplified in Example 2) compared to placebo.

FIG. 21B depicts the change in PEC score from baseline in schizophrenia patients until 6 hours post-dose of 120 μg and 180 μg dexmedetomidine sublingual film (as exemplified in Example 2) compared to placebo.

FIG. 22 depicts calming improvement in schizophrenia patients at 2 hours and 4 hours following administration of 120 μg (middle bar) and 180 μg dexmedetomidine (right bar) sublingual film (as exemplified in Example 2) compared to placebo (left bar), as measured by Agitation and Calmness Evaluation Scale (ACES).

FIG. 23 depicts percent response in schizophrenia patients at 30 minutes, 60 minutes, 120 minutes and 240 minutes following administration of 120 μg (middle bar) and 180 μg dexmedetomidine (right bar) sublingual film (as exemplified in Example 2) compared to placebo (left bar), as measured by Clinical Global Impression-Improvement (CGI).

FIG. 24A depicts the change in PEC score from baseline in bipolar patients until 2 hours post-dose of 120 μg and 180 μg dexmedetomidine sublingual film (as exemplified in Example 2) compared to placebo.

FIG. 24B depicts the change in PEC score from baseline in bipolar patients until 6 hours post-dose of 120 μg and 180 μg dexmedetomidine sublingual film (as exemplified in Example 2) compared to placebo.

FIG. 25 depicts calming improvement in bipolar patients at 2 hours and 4 hours following administration of 120 μg (middle bar) and 180 μg dexmedetomidine (right bar) sublingual film (as exemplified in Example 2) compared to placebo (left bar), as measured by Agitation and Calmness Evaluation Scale (ACES).

FIG. 26 depicts percent response in bipolar patients at 30 minutes, 60 minutes, 120 minutes and 240 minutes following administration of 120 μg (middle bar) and 180 μg dexmedetomidine (right bar) sublingual film (as exemplified in Example 2) compared to placebo (left bar), as measured by Clinical Global Impression-Improvement (CGI).

DETAILED DESCRIPTION

Abbreviations:

ACES: Agitation-Calmness Evaluation Scale;

AD: Alzheimer disease;

AE: Adverse event;

AUC: Area under the curve;

AUClast: area under the curve, calculated to the last observable time point;

AUC0-Inf: Area under the plasma concentration-time curve from time of administration to infinity

BID: twice a day;

BMI: Body mass index;

CGI-I: Clinical Global Impression-Improvement

CGI-S: Clinical Global Impression-Severity

Cmax: maximum plasma concentration;

COWS: Clinical Opiate Withdrawal Scale;

CMAI: Cohen Mansfield Agitation Inventory

CMC: Carboxy methylcellulose

C-SSRS: Columbia Suicide Severity Rating Scale

CT: Computed tomography;

CTCAE: Common Terminology Criteria for Adverse Events;

DBP: Diastolic Blood Pressure

Dex or DEX: Dexmedetomidine

DLB: Dementia with Lewy bodies;

DLT: Dose Limiting Toxicity;

DSM: Diagnostic and Statistical Manual of Mental Disorders;

DT: Disintegration time;

ECG: Electrocardiogram;

FTD: Fronto temporal disease;

HPC: Hydroxypropyl cellulose;

HPMC: Hydroxyl propyl methyl cellulose

HR: Heart rate

ICH: International Conference on Harmonisation;

ICU— Intensive care unit;

IUD: intrauterine device

IPD: In-patient Departments;

ITT: Intent to treat Population

LAR: Legally authorized representative;

LSM: Least square mean

LS: Least square;

MedDRA: Medical Dictionary for Regulatory Activities;

MMRM: Mixed model repeated measures;

MMSE: Mini-Mental State Examination;

MRI: Magnetic resonance imaging;

MW: Molecular weight;

mm: Millimeter;

mcg: microgram;

mg: Milligrams;

μg: microgram;

ml: milliliter;

mmHG: millimeters of mercury;

msec: millisecond;

ng: nanogram;

OPD: Out-Patient Department;

PANSS: Positive and Negative Syndrome Scale;

PAS: Pittsburgh Agitation Scale;

PCRS: Placebo-Control Reminder Script;

PEC: PANSS Excitement Component;

PEO: Polyethylene oxide;

PD: Pharmacodynamic;

PK: Pharmacokinetics

PVA: Polyvinyl alcohol;

QTcF: QT interval corrected for heart rate using Fridericia's formula;

QID: Quater in die

RASS: Richmond Agitation Sedation Scale;

SAE: Serious adverse event; SOWS-Gossop: Short Opiate Withdrawal Scale of Gossop;

SAP: Statistical Analysis Plan;

SBP: Systolic Blood Pressure

SD=standard deviation;

SE=standard error

SL: Sublingual;

T_(1/2): Elimination half-life;

TEAE: treatment emergent adverse event;

Tmax: Time of maximum plasma concentration;

Wt %: Weight percentage

ULN: upper limit of normal

VAS: Visual Analog Scale;

YMRS: Young Mania Rating Scale

Definitions:

As used herein, “about” means plus or minus 10% of the indicated numerical value.

The terms “formulation” and “composition” are used interchangeably, except where otherwise clearly intended to have different meanings.

Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range “from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range can be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).

The term “a” or “an” refers to one or more of that entity. As such, the terms “a” (or “an”), “one or more” and “at least one” are used interchangeably herein. In addition, reference to e.g., “an agent” by the indefinite article “a” or “an” does not exclude the possibility that more than one of the agents are present, unless the context clearly requires that there is one and only one of the agents.

As used herein, the verb “comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. The present invention may suitably “comprise,” “consist of,” or “consist essentially of,” the steps, elements, and/or reagents described in the claims.

The term “pharmaceutically acceptable carrier” refers to a pharmacologically inert substance to be used as a carrier. As used herein, the phrase “carrier” and “excipients” are used interchangeably, except where otherwise clearly intended to have different meanings.

The term “agitation,” as used herein, means irritability, emotional outburst, impaired thinking, or excess motor and verbal activity that may occur due to either dysfunction of specific brain regions such as frontal lobes or due to dysfunction of neurotransmitter systems such as dopamine and nor-epinephrine. In the present invention, agitation also includes aggression and hyper-arousal in post-traumatic stress disorder. The agitation can be acute or chronic.

The term “the signs of agitation” includes excessive motor activity (examples include: pacing, rocking, gesturing, pointing fingers, restlessness, performing repetitious mannerisms), verbal aggression (e.g., yelling, speaking in an excessively loud voice, using profanity, screaming, shouting, threatening other people), physical aggression (e.g., grabbing, shoving, pushing, clenching hands into fists, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things), and destroying property.

The term “without significant sedation” and the like means that the patient experiences a level of sedation not greater than Level 3 on the Ramsay Sedation Scale. Level 3 means sedated but responds to commands. In some embodiments, the dexmedetomidine can be dosed to achieve a Richmond Agitation Sedation Scale (RASS) of −1 (“light sedation”).

The term “dissolvable” means the films herein are readily disintegrated, e.g., at least within about 20 minutes, following administration to the oral mucosa. Disintegration is achieved by saliva and/or other aqueous materials on the mucosal surface.

The term “neuropsychiatric conditions” includes, but is not limited to, schizophrenia, bipolar illness (bipolar disorder, bipolar mania), depression, delirium or other related neuropsychiatric conditions.

The term “an effective amount” is interchangeable with “therapeutically effective dose,” or “therapeutically effective amount,” and refers to an amount sufficient to produce the desired effect. An effective amount is sufficient to cause an improvement in a condition (e.g., agitation) of the subject.

The terms “treating,” and “treatment,” as used herein refer to curative therapy, prophylactic therapy, and/or preventative therapy and can be used interchangeably.

The term “significantly reduced” refers to a reduction level by at least 10% or higher, preferably 20% or higher, more preferably 40% or higher, even more preferably 60% or higher, still more preferably 80% or higher, and 90% or higher, as compared to a control. For example, in the context of agitation, the a skilled artisan will readily understand that the reduction can be measured in terms of well-known agitation scales, such as PEC score and CGI-I (described in more detail in the examples). As an example, when agitation is significantly reduced in a patient, the reduction can be interpreted as as those who achieve at least a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or greater reduction in PEC total score from baseline (e.g., measured at 2 hours post-dose). In some embodiments, significantly reduced agitation refers to at least a 40% reduction in PEC total score from baseline. Similarly, a significant reduction in agitation can be measured on the CGI-I scale and may refer to a patient that has a score of 1 or 2 on the CGI-I scale (e.g., measured at 1, 2, or 4 hours post-dose) or the Agitation-Calmness Evaluation Scale (ACES) scale and may refer to a patient that has a score of e.g., 3 or higher.

The term “pharmaceutically acceptable salt” refers to a salt known to be non-toxic and commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salt include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyl alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used. A preferred salt is the hydrochloride salt.

The term “film” herein includes thin films, sheets and wafers, in any shape, including rectangular, square, or other desired shape. The film can be of any desired thickness and size, such that it can be conveniently placed sub-lingually in the patient. For example, the film can be a relatively thin film having a thickness of from about 20 micrometers to about 200 micrometers or can be a somewhat thicker film having a thickness of from about 20 micrometers to about 1000 micrometers. In certain embodiments, the film can be even thicker, e.g., having a thickness greater than about 30 millimeters.

As used herein, the phrase “water-soluble polymer” refers to (i) a polymer that is at least partially soluble in water, and desirably fully or predominantly soluble in water, and/or (ii) a polymer that absorbs water. Polymers that absorb water are referred to herein as water-swellable polymers.

The term “self-supporting” means the films herein maintain structural integrity upon handling without the need for a backing layer. Some flexibility in the film is contemplated and can be desirable.

As used herein, the phrase “disposed within a polymer matrix” means that dexmedetomidine or a pharmaceutically acceptable salt thereof is incorporated directly into the polymer solution prior to the formation of the solid polymer matrix film composition.

As used herein, the phrase “deposited on the surface of a polymer matrix” means that dexmedetomidine or a pharmaceutically acceptable salt thereof is formulated as liquid composition separate from the preparation of the solid polymer matrix, and deposited onto the solid polymer, e.g., as one or more (e.g., 1, 2, or 3) micro-deposits, where it dries. The dried product is sometimes referred to herein as the “micro-deposited matrix film.” The drug liquid formulation can be in any form, including as a solution, emulsion, suspension, or dispersion.

The term “intranasal administration” means administration by the nasal route, whereby a drug is insufflated through the nose. The administration can be either topical or systemic, meaning the locally delivered drug can go on to exhibit either purely local or systemic effects.

The term “parenteral” refers to administration of a drug by injection under one or more layer of skin or mucous membrane, and can include, for example, subcutaneous, intravenous, intraperitoneal or intramuscular injection.

The term “proportion of treatment responders” is defined as those subjects exhibiting about a 40% drop in PEC score at 2 hours.

The term “clinically significant cardiovascular effects” means herein a lowering in blood pressure (hypotension) and/or heart rate (bradycardia) to the extent that medical intervention is required to address the cardiovascular side effects, where the term “medical intervention” means an intervention that more serious than administering fluids, such as an energy drink.

The disclosure of International Patent Application PCT/US2020/042618 is incorporated herein by reference in its entirety.

Active Agent

Dexmedetomidine has the IUPAC name (+) 4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. As the monohydrochloride salt, it is predominantly used as a medication for the sedation of patients during treatment in an intensive care setting or to sedate patients prior to and/or during surgical and other procedures. Such medication is currently sold under the registered trade name “PRECEDEX.”

Pharmaceutically acceptable salts of dexmedetomidine that can be used herein include generally any suitable salt that has been or can be approved by the US FDA or other appropriate foreign or domestic agency for administration to a human. Non-limiting examples of suitable pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, hydrogen sulfuric, and hydroiodic acid. Other examples include salts derived from non-toxic organic acids, including acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids, or combinations of these acid salts. Exemplary salts include dexmedetomidine hydrochloride, dexmedetomidine hydrobromide, dexmedetomidine sulfate, dexmedetomidine sulfonate, dexmedetomidine phosphate, dexmedetomidine nitrate, dexmedetomidine formate, dexmedetomidine citrate, dexmedetomidine tartrate, dexmedetomidine malate, dexmedetomidine benzoate, dexmedetomidine salicylate, dexmedetomidine ascorbate or the like. In other embodiments, deuterated forms of dexmedetomidine or a pharmaceutically acceptable salt thereof can be included.

Dosage

In some embodiments, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of between about 0.5 μg (mcg) to about 1200 μg, depending on the route of administration etc. Examples of suitable dosages include: about 0.5 μg to about 1200 μg, about 0.5 μg to about 500 μg, about 0.5 μg to about 450 μg, about 0.5 μg to about 405 μg, about 0.5 μg to about 360 μg, about 0.5 μg to about 270 μg, about 0.5 μg to about 180 μg, and about 0.5 μg to about 120 μg. In some embodiments, the dose is 180 μg, 120 μg, 90 μg, or 60 μg.

In embodiments of the method, the dosage of dexmedetomidine is defined as the amount of dexmedetomidine free base or an equivalent amount of pharmaceutically acceptable salt thereof administered.

The dose can be administered one or more times a day including once, twice, three times, four times, five times or six times per day. In some embodiments, the dose can be administered one time a day or two times a day, and in other embodiments, the dose can be administered three times a day so long as the maximum total daily (i.e., a 24 hour period) dose is not exceeded. In some embodiments, the first (i.e., initial) daily dose is higher than the optional second dose or optional third dose. In some embodiments, the first (i.e., initial) daily dose is 180 μg, 120 μg, 90 μg, or 60 μg. In some embodiments subsequent doses (e.g., a second dose, a third dose) are 60 μg. In some embodiments, a dose of 90 μg or 60 μg can be provided by cutting an oromucosal formulation (e.g., an oromucosal film) comprising 180 μg or 120 μg, respectively, in half.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered at a dose of about 10 μg to about 300 μg, e.g., about 10 μg to 270 μg, about 20 μg to about 240 μg, about 30 μg to about 180 μg, about 40 μg to about 140 μg, about 60 μg to about 120 μg, about 70 μg to about 100 μg, about 80 μg to about 100 μg of unit dose total weight of pharmaceutical composition. These doses can be provided via one or more units to deliver the total dose. Examples of suitable doses include (in μg): about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245 and about 250.

In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof are administered oromucosally (e.g., sublingually or buccally) at a dose of about 10 μg to about 300 μg, e.g., about 10 μg to 270 μg, about 20 μg to about 240 μg, about 30 μg to about 180 μg, about 40 μg to about 140 μg, about 50 μg to about 120 μg, about 60 μg to about 120 μg, about 70 μg to about 100 μg, about 80 μg to about 100 μg of unit dose total weight of sublingual film composition. These doses can be provided via one or more units to deliver the total dose. Examples of suitable doses include (in μg): about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245 and about 250.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered at a dose of about 120 μg to about 405 μg, e.g., about 120 μg to about 270 μg, including about 120 μg and about 180 μg of unit dose total weight of pharmaceutical composition. These doses can be provided via one or more units to deliver the total dose. Examples of suitable doses include (in μg): about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 395, about 400 and about 405.

In another embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered oromucosally (e.g., sublingually or buccally) at a dose of about 120 μg to about 405 μg, e.g., about 120 μg to about 270 μg, including about 120 μg and about 180 μg of unit dose total weight of sublingual film composition. These doses can be provided via one or more units to deliver the total dose. Examples of suitable doses include (in μg): about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 395, about 400 and about 405.

The exemplary dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof to be administered to a particular patient, will depend on the type and extent of the condition, the overall health status of the particular patient, the particular form of dexmedetomidine or a pharmaceutically acceptable salt thereof being administered, and the particular formulation used to treat the patient.

Pharmaceutical Compositions

According to the present disclosure, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered to the human subject through the oromucosa (e.g., sublingually, buccally). Formulations suitable for use according to the present disclosure are outlined below. Additional formulations suitable for use according to the present disclosure are described in US 2020/0000717, which is hereby incorporated by reference in its entirety for all purposes.

Dexmedetomidine or a pharmaceutically acceptable salt thereof can be formulated, according to the present disclosure, into dosage forms suitable for sublingual or buccal administration. Such dosage forms include tablets, powders, pills, films, capsules, liquids, gels, syrups, slurries, suspensions, and the like. In one embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is formulated as a film product.

Carriers suitable for inclusion in sublingual or buccal formulations include, but are not limited to, sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulphate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, pyrogen-free water and combinations thereof. Carriers which readily dissolve in saliva can be used.

Sublingual or buccal formulations may also include other pharmaceutically acceptable carriers and/or excipients such as binders, lubricants, diluents, coatings, disintegrants, barrier layer components, glidants, colouring agents, solubility enhancers, gelling agents, fillers, proteins, co-factors, emulsifiers, solubilising agents, suspending agents and mixtures thereof. Particular excipients, which can be used according to this disclosure, are known in the art, for example as described in Handbook of Pharmaceutical Excipients, fifth edition, 2005 edited by Rowe et al., Mcgraw Hill.

Films

Suitable films for sublingual or buccal administration (i.e. oromucosal administration) according to the present disclosure comprise dexmedetomidine or a pharmaceutically acceptable salt thereof either (i) disposed within a polymer matrix or (ii) deposited on the surface of a polymer matrix, e.g., on the surface of a “placebo” film.

The polymer component consists of one or more water-soluble polymers within the film matrix and/or as part of the drug-containing deposit (e.g., one or more droplets) on the surface of the polymer. In some embodiments of the disclosure, the polymer component consists of a single water-soluble polymer. In some embodiments, the polymer component consists of two or more water-soluble polymers, including two or more of the same water-soluble polymers having different molecular weights.

The polymer component in the film matrix is of a suitable composition and present in a sufficient amount to ensure rapid disintegration of the film matrix in the oral mucosa. For example, the presence of the polymer component may allow the film matrix to disintegrate completely oromucosally in about 15 seconds to about 180 seconds, for example, about 30 seconds to about 180 seconds, including about 120 seconds. The polymer component in the film matrix also provides the film with sufficient strength (i.e. the film is self-supporting).

When present in one or more droplets of the dexmedetomidine composition deposited onto the surface of the polymer matrix/substrate, the polymer component may, for example, consist of the water-soluble polymer hydroxypropyl cellulose, although different water-soluble polymers are also contemplated as described hereinafter under the definition “first water-soluble polymer” and “second water soluble polymer.” For example, the polymer component may consist of one, two or three hydroxypropyl celluloses having different molecular weights. The molecular weights of the different hydroxypropyl celluloses may conveniently range from (i) less than about 60,000 daltons (e.g., about 5,000 daltons to about 49,000 daltons) (ii) about 90,000 daltons to about 200,000 daltons and (iii) about 200,000 daltons to about 500,000 daltons. The two or more hydroxypropyl celluloses can be mixed in any suitable ratio to achieve the desired droplet viscosity. The viscosity of the dexmedetomidine composition solution or suspension can be measured using a Brookfield viscometer with a small sample adapter at a temperature of 25° C. and may range from about 5 cps to about 3700 cps. For example, it may range from about 5 cps to about 500 cps, about 6 cps to about 200 cps, about 6 cps to about 100 cps or about 6 cps to about 50 cps. In some embodiments of the present disclosure, the viscosity of the dexmedetomidine composition solution or suspension is from about 6 cps to about 20 cps at 25.0 and a shear rate of about 7 (1/s).

When present in a monolithic (i.e. placebo or drug-containing) film, the polymer component may, for example, consist of one water soluble polymer or two different water-soluble polymers. When two different water-soluble polymers are present, one of the water-soluble polymers may include the same polymer but present in the polymer component as a combination of different molecular weights. For example, the polymer component may consist of one, two or three hydroxypropyl celluloses having different molecular weights, although different water-soluble polymers are also contemplated as described hereinafter under the definition “first water-soluble polymer” and “second water soluble polymer” such as polyethylene oxide. The molecular weights of the different hydroxypropyl celluloses may conveniently range from (i) less than about 60,000 daltons (e.g., about 5000 daltons to about 49000 daltons) (ii) about 90000 daltons to about 200000 daltons and (iii) about 200,000 daltons to about 500,000 daltons (e.g., about 300000 daltons to about 450000 daltons). The two or more hydroxypropyl celluloses (e.g., low and high molecular weight hydroxypropyl celluloses) can be mixed in any suitable ratio to achieve the desired film properties. When present in a monolithic (i.e. placebo or drug-containing) film or micro-deposited film matrix composition, the polymer component may conveniently consist of one or more water-soluble polymers having a molecular weight less than about 60,000 daltons (e.g., about 5,000 daltons to about 49,000 daltons), and/or from about 90000 daltons to about 200,000 daltons and/or about 200,000 daltons to about 500,000 daltons (e.g., about 300000 daltons to about 450000 daltons). When a structurally different water-soluble polymer is also present, it may conveniently have a higher molecular weight, for example a molecular weight greater than about 500,000 daltons.

In some embodiments, the disclosure provides pharmaceutical film compositions, comprising: (i) dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a polymer component consisting of a first water-soluble polymer having a molecular weight less than about 60,000 daltons (e.g., about 5,000 daltons to about 49,000 daltons), and one or more second-water soluble polymers having a molecular weight greater than about 60,000 daltons; and, optionally, (iii) one or more pharmaceutically acceptable carriers.

In some embodiments, the disclosure provides pharmaceutical film compositions consisting essentially of: (i) dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a polymer component consisting of a first water-soluble polymer having a molecular weight less than about 60,000 daltons (e.g., about 5,000 daltons to about 49,000 daltons), and one or more second-water soluble polymers having a molecular weight greater than about 60,000 daltons; and, optionally, (iii) one or more pharmaceutically acceptable carriers.

In some embodiments, the disclosure provides pharmaceutical film compositions consisting of: (i) dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a polymer component consisting of a first water-soluble polymer having a molecular weight less than about 60,000 daltons (e.g., about 5,000 daltons to about 49,000 daltons), and one or more second water-soluble polymers having a molecular weight greater than about 60,000 daltons; and, optionally, (iii) one or more pharmaceutically acceptable carriers.

Examples of one or more first water-soluble polymers are selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, methyl cellulose and mixtures thereof, including mixtures of the same polymer having different molecular weights.

Examples of one or more second water-soluble polymers are selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxy methylcellulose, methylcellulose and mixtures thereof, including mixtures of the same polymer having different molecular weights. Polyethylene oxide (PEO) may also be present herein as a second water-soluble polymer or can be described separately hereinafter in the pharmaceutical film compositions as an example of a pharmaceutically acceptable carrier, or more particularly, as a mucoadhesive agent.

In one embodiment, the weight ratio of said first water-soluble polymer to said second water-soluble polymer(s) (including PEO when present in the film) in the entire film composition is from about 2:1 to about 1:50, for example about 1:1 to about 1:40, including about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, about 1:20, about 1:21, about 1:22, about 1:23, about 1:24, about 1:25, about 1:26, about 1:27, about 1:28, about 1:29, about 1:30, about 1:31, about 1:32, about 1:33, about 1:34, about 1:35, about 1:36, about 1:37, about 1:38, about 1:39, or about 1:40.

In a further embodiment, the weight ratio of said first water-soluble polymer to said second water-soluble polymer(s) (including PEO when present in the film) in the entire film composition is from about 1:10 to about 1:30, about 1:15 to about 1:25 or about 1:15 to about 1:20. In some embodiments, a ratio of about 1:15 to about 1:20 provides beneficial functional effects.

Examples of other water-soluble polymers which can be included in the film with the first water-soluble polymer/second water-soluble polymer or replace such polymer(s) include povidone (polyvinylpyrrolidone), copovidone (copolymers of N-vinyl-2-pyrrolidone and vinyl acetate), polyvinyl alcohol, polyethylene glycol, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, polydextrose, pullulan, carboxymethyl cellulose, sodium alginate, chitosan, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, starch, carrageenan, gelatin and mixtures thereof. The water-soluble polymer component, including water-soluble polymer carriers when present, may conveniently comprise about 40% to about 99.8%, about 50% to about 99.7%, about 60% to about 99.6% of the film composition, based on the weight of the film on a dry weight basis.

In some embodiments, the polymer component for the film composition comprises a first water-soluble polymer present in an amount of from about 2% to about 15% on a dry weight basis of the polymer component (e.g., at about 3% to about 8% w/w of the total film weight). This water-soluble polymer may conveniently have a molecular weight from about 5,000 daltons to about 49,000 daltons. Examples of suitable such water-soluble polymers include those selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methyl cellulose, and mixtures thereof.

In some embodiments, low molecular weight hydroxypropyl cellulose can be present in the film at about 3% to about 8% w/w of the total film weight.

In some embodiments, the one or more second water-soluble polymers (including water-soluble polymer carriers such as polyethylene oxide) may, for example, be present in an amount of from about 50 to about 98 weight percent on dry weight basis of the polymer component. The one or more second water-soluble polymers each has a molecular weight greater than 60,000 daltons; for example, from about 90,000 daltons to about 1,500,000 daltons, especially when the polymer is selected from the group consisting of polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxy methylcellulose, methylcellulose, and mixtures thereof.

In some embodiments, the one or more second water-soluble polymers may together be present in the film at about 25% to about 40% w/w of the total film weight when the one or more second water-soluble polymers each has a molecular weight from about 90,000 daltons to about 200,000 daltons and/or from about 200,000 daltons to about 500,000 daltons, and the polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxy methylcellulose, methylcellulose, and mixtures thereof.

In some embodiments, a polyethylene oxide can be present in the film at about 50% to about 60% w/w of the total film weight.

In one embodiment, the polymer component for the film composition consists of a low molecular weight, water-soluble polymer (e.g., having a molecular weight less than about 60,000 daltons) and one or more high molecular weight polymers (e.g., having a molecular weight greater about 60,000, up to about 1,500,000 daltons when a polyethylene oxide is included in the polymer mixture or up to about 500,000 daltons when a polyethylene oxide is not included in the polymer mixture). This polymer combination, especially when the polymers are a combination of hydroxypropyl cellulose and polyethylene oxide, lends certain advantages to the tensile strength and pharmacokinetics of the film composition.

In some embodiments, the oromucosal formulation is a film composition comprising (e.g., consisting essentially of):

-   -   (i) a therapeutically effective amount of dexmedetomidine or a         pharmaceutically acceptable salt thereof;     -   (ii) a polymer component consisting of one or more water-soluble         polymers: and     -   (iii) one or more pharmaceutically acceptable carriers.

In one embodiment, the oromucosal formulation is a film composition comprising (e.g., consisting essentially of):

-   -   (i) therapeutically effective amount of dexmedetomidine or a         pharmaceutically acceptable salt thereof;     -   (ii) a polymer component consisting of: (a) one or more first         water-soluble polymer (e.g., hydroxypropyl cellulose,         hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxy         methylcellulose, methylcellulose, and mixtures thereof) having a         molecular weight from about 5,000 daltons to about 49,000         daltons, for example, in about 2 to about 15 weight percent on         dry weight basis of the total polymer component; and (b) one or         more second water-soluble polymers (e.g., polyethylene oxide,         hydroxypropyl cellulose, hydroxypropyl methylcellulose,         hydroxyethyl cellulose, carboxy methylcellulose,         methylcellulose, and mixtures thereof) having a molecular weight         greater than 60,000 daltons, such as greater than 100000         daltons, for example in about 50 to about 98 weight percent on         dry weight basis of the total polymer component; and     -   (iii) one or more pharmaceutically acceptable carriers.

The molecular weight of hydroxypropyl cellulose, when present in the film of the present disclosure, can be varied, and can be present as both a low molecular weight, water-soluble polymer and as one or more high molecular weight, water-soluble polymers. In some embodiments, the molecular weight can be less than about 60,000 daltons (e.g., about 5,000 daltons to about 49,000 daltons). In other embodiments the molecular weight can be in the range from about 90,000 daltons to about 200,000 daltons. In yet other embodiments, the molecular weight can be in the range from about 200,000 daltons to about 500,000 daltons.

Hydroxypropyl cellulose, when part of the film composition including polyethylene oxide, may conveniently be present in the range from about 10% to about 90% by weight on a dry weight basis of the polymer component, e.g., about 20% to about 80% by weight on dry weight basis of the polymer component, e.g., about 20% to about 50% by weight on dry weight basis of the polymer component, e.g., about 25% to about 45% by weight on dry weight basis of the polymer component.

The molecular weight of polyethylene oxide, when present in the film of the present disclosure, may also be varied. In some embodiments, a water-soluble, high molecular weight polyethylene oxide can be used, for example, to increase muco-adhesivity of the film. In certain embodiments, the molecular weight may range from about 100,000 daltons to about 1,500,000 daltons, including about 100,000, 200,000, 300,000, 600,000, 900,000 or 1,000,000 daltons. In some embodiments, it can be desirable to use a combination of polyethylene oxide having a molecular weight of about 600,000 daltons to about 900,000 daltons with polyethylene oxide having a molecular weight of about 100,000 daltons to about 300,000 daltons in the polymer component.

Polyethylene oxide, when part of the film composition, may conveniently be present range from about 30% to about 90% by weight on a dry weight basis of the total polymer component, e.g., about 40% to about 85% by weight on a dry weight basis of the polymer component, e.g., about 55% to about 80% by weight on a dry weight basis of the polymer component.

Such film compositions may contain the drug dispersed within the film, or micro-deposited onto a surface of the film. When micro-deposited on the surface of a “placebo” film, the drug may conveniently be added as part of a dexmedetomidine composition as one or more droplets in a liquid carrier, such as a solvent (e.g., an alcohol such as ethanol), optionally together with one or more (e.g., one, two, three, or four) water-soluble polymers and/or pharmaceutically acceptable carriers. Suitable water-soluble polymers include (1) a low molecular weight, water-soluble polymer, for example a low molecular weight, water-soluble polymer having a molecular weight of less than about 60,000 daltons (e.g., a molecular weight of about 5,000 daltons to about 49,000 daltons and optionally (2) one or more (e.g., one or two) high molecular weight, water-soluble polymers, for example a high molecular weight, water-soluble polymer having a molecular weight of greater than about 60,000 daltons (e.g., a molecular weight of from about 60,000 daltons to about 150,000 daltons such as hydroxypropyl cellulose (77,000 MW), hydroxypropyl cellulose (80,000 MW), hydroxypropyl cellulose (90,000 MW), or hydroxypropyl cellulose (140,000 MW)) and/or a high molecular weight, water-soluble polymer having a molecular weight of greater than about 60,000 daltons (e.g., a molecular weight of from about 200,000 daltons to about 900,000 daltons such as hydroxypropyl cellulose (340,000 MW), hydroxypropyl cellulose (370,000 MW), polyethylene oxide (200,000 MW) or polyethylene oxide (600,000 MW)). Each water-soluble polymer may independently be selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyethylene oxide and methyl cellulose, e.g., hydroxypropyl cellulose and/or polyethylene oxide.

In some embodiments, the dexmedetomidine composition comprises dexmedetomidine hydrochloride, a low molecular weight polymer which is hydroxypropyl cellulose and one or two high molecular weight polymers which are each hydroxypropyl cellulose in an ethanol solvent.

In one embodiment, the dexmedetomidine composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride), hydroxypropyl cellulose (40,000 MW) and one or both of hydroxypropyl cellulose (140,000 MW) and hydroxypropyl cellulose (370,000 MW).

In another embodiment, the dexmedetomidine composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride), and only two hydroxypropyl celluloses, namely hydroxypropyl cellulose (40,000 MW) and hydroxypropyl cellulose (140,000 MW).

In some embodiments, the deposition composition can be in any form, including as a solution, emulsion, suspension or dispersion. For example, the dexmedetomidine composition can be added as one or more droplets in an ethanol-based solution, optionally containing a pH-neutralizing agent such as sodium hydroxide. In some embodiments, the film substrate surface contains two or more micro-deposited spots of dexmedetomidine hydrochloride (e.g., two microdeposited spots) in a polymer matrix. The viscosity of deposition solution/suspension may range from about 6 cps to about 3700 cps as measured at 25° C. using a Brookfield viscometer with a small sample adapter. As an example, it may range from about 5 cps to about 500 cps, about 6 cps to about 200 cps, about 6 cps to about 100 cps or about 6 cps to about 50 cps.

In some embodiments of the present disclosure, the viscosity of the dexmedetomidine composition is from about 6 cps to about 20 cps at 25° C. and a shear rate of about 7 (Us).

Following drying to remove the solvent, the film comprises a film substrate (e.g., a placebo) with the dexmedetomidine composition as previously described but absent the solvent deposited (e.g., micro-deposited) on the surface of the film substrate. The dried composition containing dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) may cover the whole of the film substrate surface or only part of the film substrate surface.

In some embodiments, the dried dexmedetomidine composition appears as one or more discrete drug-containing droplets on the film substrate surface. Alternatively, stenciling can be used to achieve a one or more defined and discrete regions of drug-containing composition on the surface of the film substrate.

In some embodiments, the disclosure provides a dry film product comprising a film substrate with one or more discrete drug-containing droplets on the film substrate surface, wherein each such drug-containing droplet comprises dexmedetomidine or a pharmaceutically acceptable salt thereof, and hydroxypropyl cellulose of two molecular weights: hydroxypropyl cellulose (40,000 MW) available as HPC-SSL, and hydroxypropyl cellulose (140,000 MW) marketed under the tradename of Klucel™ Type JF NF, and wherein the film substrate comprises hydroxypropyl cellulose of three molecular weights: hydroxypropyl cellulose (40,000 MW), hydroxypropyl cellulose (140,000 MW), and hydroxypropyl cellulose (370,000 MW) marketed under the tradename of Klucel™ Type GF NF. In some embodiments, the film substrate also comprises polyethylene oxide (600,000 MW) available under the name of Sentry Polyox WSR 205 LEO NF.

In some embodiments, the dry film product comprises a deposition composition (also referred to herein as a “dexmedetomidine composition”) comprising: (i) dexmedetomidine hydrochloride, present at about 9% to about 50% w/w of the deposition composition, e.g., about 15% to about 25% w/w of the deposition composition; (ii) hydroxypropyl cellulose (40,000 MW), present at about 5% to about 85% w/w of the deposition composition; (iii) hydroxypropyl cellulose (140,000 MW) present at about 5% to 85% w/w of the deposition composition; and (iv) hydroxypropyl cellulose (370,000 MW) present at about 0% to about 65% w/w of the deposition composition. The film also comprises a polymer matrix, wherein the polymer matrix comprises: (i) hydroxypropyl cellulose (40,000 MW) present at about 3% to about 40% w/w of the polymer matrix; (ii) hydroxypropyl cellulose (140,000 MW) present at about 3% to about 40% w/w of the polymer matrix; (iii) hydroxypropyl cellulose (370,000 MW) present at about 0% to about 30% w/w of the polymer matrix, and (iv) polyethylene oxide (600,000 MW) present at about 55% to about 75% w/w of the polymer matrix.

In some embodiments, the dry film product (e.g., a micro-deposited film product) comprises (i) dexmedetomidine hydrochloride, present at about 1% to about 50% w/w of the total film weight; (ii) hydroxypropyl cellulose (40,000 MW), present at about 2% to about 30% w/w of the total film weight; (iii) hydroxypropyl cellulose (140,000 MW) present at about 2% to about 30% w/w of the total film weight; (iv) hydroxypropyl cellulose (370,000 MW) present at about 10% to about 50% w/w of the total film weight, (v) polyethylene oxide (600,000 MW) present at about 40% to about 75% w/w of the total film weight and (vi) optionally other pharmaceutically acceptable carriers.

In some embodiments, the films disclosed herein combine several types of hydroxypropyl cellulose (HPC) to provide a film with advantageous properties. For example, the film composition may contain two or three of hydroxypropyl cellulose (40,000 MW), hydroxypropyl cellulose (140,000 MW) and hydroxypropyl cellulose (370,000 MW) in combination. In certain embodiments, polyethylene oxide (600,000 MW) is included with these types of HPC when part of a monolithic film.

In certain film compositions of the present disclosure, a low molecular weight hydroxypropyl cellulose (e.g., 40,000 MW) is present at about 3% to about 8% (e.g., about 5%) w/w of the total film weight, a high molecular weight hydroxypropyl cellulose (e.g., 140,000 MW) is present at about 3% to about 8% (e.g., about 5%) w/w of the total film weight, a high molecular weight hydroxypropyl cellulose (e.g., 370,000 MW) is present at about 20% to about 40% w/w of the total film weight, and a polyethylene oxide (e.g., 600,000 MW) is present at about 40% to about 70%, (e.g., about 50% to about 60%) w/w of the total film weight. In some embodiments, the two high molecular weight, water-soluble polymers are together present at about 25% to about 40% w/w of the total film weight.

The selection and ratio of water-soluble polymers can be made to effect complete dissolution of the film composition in oral mucosal fluids within seconds to minutes, e.g., in about 0.25 minutes to about 15 minutes, thus ensuring delivery of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof via the oral mucosa. For example, the film compositions may reside in the sublingual or buccal region of the mouth up to about 15 minutes, up to about 10 minutes, or up to about 5 minutes, including for a period of from about 30 seconds to about 15 minutes, about 1 minute to about 10 minutes, or about 1 minute to about 5 minutes.

The standard basket or paddle apparatus described in any pharmacopoeia can be used for in vitro dissolution testing. The selection of dissolution medium will essentially depend as per the sink conditions and highest dose of drug. The temperature of dissolution medium should be maintained at 37±0.5° C. and rpm at 50 (see Bala et al., Int J Pharm Investigation, 2013, vol. 3(2), pages 67-76).

Films disclosed herein have several functional advantages to promote rapid onset of drug effect. In some embodiments, thin films compositions of the disclosure have a disintegration time (DT) of about 15 seconds to about 180 seconds, about 15 seconds to about 160 seconds, about 25 seconds to about 150 seconds, about 15 seconds to about 140 seconds, about 15 seconds to about 120 seconds, about 40 seconds to about 120 seconds, about 50 seconds to about 120 seconds, for example about 120 seconds, when applied sublingually or buccally. A disintegration time in this time-frame provides optimal onset of drug effects.

In some embodiments, thin film compositions of the invention have mucoadhesion properties that provide practical benefits of localizing the film to the sublingual location and reducing, or preventing, effective removal prior to dissolution. This quality is particularly advantageous in a clinical setting with an agitated subject. Thus, in some embodiments, thin film compositions have a mucoadhesion force (the mucoadhesion strength or shear strength) of about 50 g or above, about 100 g or above, about 200 g or above, about 300 g or above, about 400 g or above, about 500 g or above, about 600 g or above, about 700 g or above, about 800 g or above, about 900 g or above, about 1000 g or above. In some embodiments, the mucoadhesion force is in a range of about 300 g to about 4000 g, about 500 g to about 3000 g, or about 1000 g to about 2000 g.

Burst strength of the film also contributes to drug delivery. Certain thin film compositions of the invention have a burst strength at or above 50 g, 100 g, 200 g, 300 g, 400 g, 500 g, 600 g, 700 g, 800 g, 900 g, 1000 g, 1100 g, 1200 g, 1300 g, 1400 g, 1500 g, 1600 g, 1700 g, 1800 g, 1900 g, 2,000 g, 2,500 g, 3,000 g, 3,500 g, 4,000 g, 4,500 g, 5,000 g, 5,500 g, 6,000 g, 6,500 g, 7,000 g, 7,500 g, 8,000 g, 8,500 g, 9,000 g, 9,500 g, 10,000 g or 15,000 g. For example, the burst strength can be in a range of about 200 g to about 15000 g, about 300 g to about 10,000 g, or 400 g to about 5,000 g.

Pharmaceutically Acceptable Carriers

The film compositions can further comprise one or more pharmaceutically acceptable carriers that includes, but is not limited to, liquid carriers, flavours, sweeteners, refreshing agents, antioxidants, pH adjusting agents, permeation enhancers, mucoadhesive agents, plasticizers, bulking agents, surfactants/non-ionic solubilizers, stabilizers, anti-foam agents, colors or the like. In certain embodiments, the film compositions are substantially free of acidic buffer or other acidic agents.

Liquid Carriers

According to some embodiments, the pharmaceutically acceptable carrier includes a liquid carrier. The liquid carrier comprises one or more solvents useful in the preparation of the polymer matrix (drug containing or placebo) and deposition composition on the polymer matrix. In some embodiments, the solvent can be water. In some embodiments, the solvent may a polar organic solvent including, but are not limited to, ethanol, isopropanol, acetone, butanol, benzyl alcohol and mixtures thereof. In some embodiments, the solvent can be a non-polar organic solvent, such as methylene chloride, toluene, ethyl acetate and mixtures thereof. Certain solvents are alcohols, especially ethanol, water and mixtures thereof. Desirably, the solvent content in the wet polymer matrix is at least about 30% by weight of the total wet weight of the total film composition prior to drying. The subsequent dried film composition will desirably contain less than about 10% by weight of solvent, more desirably less than about 8% by weight of solvent, even more desirably less than about 6% by weight of solvent and most desirably less than about 2% by weight of solvent.

Flavors/Sweeteners/Refreshing Agents

It can be beneficial to add a sweetener, flavoring agent, refreshing agent, taste-masking agent or a combination thereof to the film compositions to improve the film composition taste. Flavors can be chosen from natural and synthetic flavoring liquids. An illustrative list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. Non-limiting flavor oils include: spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, and oil of bitter almonds. In one embodiment, the flavor is a peppermint oil flavour available as peppermint oil, NF.

The amount can be varied in order to obtain the result desired in the final product. Such variations are within the capabilities of those skilled in the art without the need for undue experimentation. In general, amounts of about 0.1% to about 30 wt % can be used in the films to supply flavoring. Suitable sweeteners include both natural and artificial sweeteners. Non-limiting examples of suitable sweeteners include, e.g.: water-soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), high fructose corn syrup, maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, and dihydrochalcones; water-soluble artificial sweeteners such as the soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts and water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, such as a chlorinated derivatives of ordinary sugar (sucrose), known, for example, as sucralose. In one embodiment, the sweetener is sucralose.

Flavoring agents, sweeteners and refreshing agents can be added in conventional quantities, generally up to a total amount of about 0.01% to about 10% of the weight of the film on a dry weight basis, e.g., from about 0.1% to about 7% of the weight of the film on a dry weight basis, e.g., about 0.1% to about 5% based on the weight of the film on a dry weight basis.

Other taste-masking agents include, for example polymers, oils, or waxes. In one embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is coated with a taste-masking agent prior to formulation of the film compositions. In some embodiments, if a taste-masking agent is used to coat the active ingredient, it can be present in an amount of from about 5% to about 80% by weight of the particle or granule containing the active ingredient. In another embodiment, the taste-masking agent is present in an amount from about 25% to about 35% by weight of the particle or granule containing the active ingredient.

Antioxidants

Examples of oxygen scavengers or antioxidants that substantially improve long-term stability of the film composition against oxidative degradation include sulfite salts, such as sodium sulfite, sodium bisulfite, sodium metabisulfite and analogous salts of potassium and calcium. A suitable amount of the sulfite salt (e.g., sodium sulfite) is up to about 5%, e.g., about 0.001% to about 2% based on the weight of the film composition on a dry weight basis.

pH-Adjusting Agents/pH-Neutralizing Agents

The absorption of dexmedetomidine or a pharmaceutical acceptable salt thereof through the oral mucosa may increase in an alkaline microenvironment. As an example, this can be achieved when the film compositions are maintained at a pH of above 6, from about 6 to about 9, or about 6.5 to about 8. In some embodiments, the film may include an alkaline substance that increases the pH of the film product. Non-limiting examples of pH-adjusting/pH-neutralizing agents include bicarbonates (e.g., sodium bicarbonate), citrates (e.g., potassium citrate), carbonates (e.g., calcium carbonate), lactates (e.g., sodium lactate), acetates (e.g., calcium acetate), alkaline buffer (e.g., glycine), sodium hydroxide, sodium chloride or the like. An alkaline buffer, such as glycine, is one example of a pH-neutralizing agent. A suitable amount of pH-adjusting/pH-neutralizing agent present in the film composition includes, for example, up to about 10%, e.g., about 1% to about 5% based on the weight of the film composition on a dry weight basis

Permeation Enhancer Agents

Certain effective penetration enhancers that promote absorption of dexmedetomidine or a pharmaceutically acceptable salt thereof across the oral mucosa include alcohols. An alcohol penetration enhancer, such as butanol, can conveniently be added to the film composition in an amount of up to about 10%, e.g., about 0.1% to about 5%, e.g., about 1% to about 3% based on the weight of the film composition on a dry weight basis.

Mucoadhesive Agents

Examples of mucoadhesive agents that can be added to the film composition include, but are not limited to, sodium alginate, sodium carboxymethyl cellulose, guar gum, polyethylene oxide, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, karaya gum, methylcellulose, retene, tragacanth and the like. One mucoadhesive agent is polyethylene oxide, which may conveniently be added to the film composition in an amount of from about 20% to about 90%, e.g., about 40% to about 70% based on the total weight of the film composition on a dry weight basis.

Plasticizers

Plasticizers that can be effectively employed herein include polyethylene glycol, propylene glycol, tributyl citrate, triethyl citrate and glycerol. Depending on the selected film-forming polymer(s) and other components of the film formulation, a suitable amount of plasticizer included in the film composition may typically be up to about 10%, e.g., about 0.1% to about 5%, e.g., about 0.5% to about 5% based on the weight of the film on a dry weight basis. For certain applications, higher molecular weight polyethylene glycols can be utilized, including polyethylene oxide

Fillers

Suitable fillers that can be added to a film composition of include starch, calcium salts, such as calcium carbonate, and sugars, such as lactose, glucose, sucrose, mannose, sorbitol, mannitol, galactitol, sucralose, trehalose and combinations thereof. The amount of filler that can conveniently be added to the film formulation is typically up to about 25%, e.g., about 0.5% to about 20%, e.g., about 1% to about 15%, e.g., about 2% to about 10%, based on the weight of the film composition on a dry weight basis.

Surfactants/Non-Ionic Solubilizers

The film typically incorporates at least one surfactant/non-ionic solubilizer including, for example, but are not limited to, a poloxamer, polyoxyl hydrogenated castor oil, glyceryl polyethylene glycol oxystearates, fatty acid glyceryl polyglyceryl esters, polyglyceryl esters, and combinations thereof. The amount of surfactant(s) that can be added to the film composition is typically up to about 5%, e.g., about 0.5% to about 3%, e.g., about 1% to about 3% based on the weight of the film composition on a dry weight basis.

Anti Foaming Components

Simethicone is an example of a useful anti-foaming and/or de-foaming agent, although other anti-foaming and/or de-foaming agents may suitable be used. An anti-foaming and/or de-foaming agent such as simethicone can be added to the film composition in an amount from about 0.01% to about 5.0%, more desirably from about 0.05% to about 2.5%, and most desirably from about 0.1% to about 1.0% based on the weight of the film composition on a dry weight basis.

Colorants

Color additives that can be included in a film composition include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors are dyes, their corresponding lakes, and certain natural and derived colorants. Certain examples of color additives are inorganic pigments, such as oxides of iron or titanium, added in concentrations ranging from about 0.001% to about 10%, e.g., about 0.01% to about 3%, based on the weight of the film composition on a dry weigh basis. In one embodiment, the color used for the dexmedetomidine composition (i.e. the deposit composition) is different from the color used for the film substrate (e.g., the placebo film). One color of the monolithic film and the film substrate of the micro-deposited film is emerald green, and available as Fast Emerald Green Shade (06507). One color of the dexmedetomidine composition (i.e. the deposit composition) is a different color from the color of the film substrate, e.g., blue (available as FD&C Blue No. 1). In some embodiments of the film embodiments of the present invention, for example, as described in aspects and embodiments hereinabove, is a film comprising about 180 μg or about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof containing two blue color microdeposited spots of dexmedetomidine hydrochloride on the green color film substrate.

In one embodiment, the oromucosal formulation is a self-supporting, dissolvable, film, comprising:

-   -   (i) about 180 μg of dexmedetomidine or a pharmaceutically         acceptable salt thereof (e.g., the hydrochloride salt);     -   (ii) one or more water-soluble polymers;     -   (iii) a polyethylene oxide and, optionally,     -   (iv) one or more pharmaceutically acceptable carriers.

In another embodiment, the oromucosal formulation is a self-supporting, dissolvable, film, comprising:

-   -   (i) about 120 μg of dexmedetomidine or a pharmaceutically         acceptable salt thereof (e.g., the hydrochloride salt);     -   (ii) one or more water-soluble polymers;     -   (iii) a polyethylene oxide and, optionally,     -   (iv) one or more pharmaceutically acceptable carriers.

In a particular embodiment, the just-mentioned one or more water-soluble polymers (ii) comprises a low molecular weight, water-soluble polymer and two high molecular weight, water-soluble polymers, for example wherein the low molecular weight, water-soluble polymer has a molecular weight from about 5,000 daltons to about 49,000 daltons (e.g., about 40,000 daltons), and each high molecular weight, water-soluble polymer has a molecular weight of greater than about 60,000 daltons (e.g., where one of the two high molecular weight, water-soluble polymers has a molecular weight of about 140,000 daltons, and the other high molecular weight, water-soluble polymer has a molecular weight of about 370,000 daltons). Each water-soluble polymer is, in some embodiments, hydroxypropyl cellulose. The polyethylene oxide, in some embodiments, has a molecular weight of about 600,000 daltons.

In certain embodiments, there is provided a pharmaceutical film composition comprising or consisting essentially of therapeutically effective amount of dexmedetomidine or pharmaceutically acceptable salt thereof and one or more excipients selected from polyethylene oxide, hydroxypropyl cellulose, sucralose, peppermint oil, Emerald green colorant, and FD&C blue colorant.

In another embodiment, the oromucosal formulation is a self-supporting, dissolvable, film, comprising:

-   -   (i) about 180 μg of dexmedetomidine or a pharmaceutically         acceptable salt thereof (e.g., the hydrochloride salt);     -   (ii) a low molecular weight, water-soluble polymer having a         molecular weight of about 40,000 daltons;     -   (iii) a high molecular weight, water-soluble polymer having a         molecular weight from about 140,000 daltons;     -   (iv) a high molecular weight, water-soluble polymer having a         molecular weight from about 370,000 daltons; and     -   (v) a water-soluble polyethylene oxide having a molecular weight         of about 600,000 daltons.

In another embodiment, the oromucosal formulation is a self-supporting, dissolvable, film, comprising:

-   -   (i) about 120 μg of dexmedetomidine or a pharmaceutically         acceptable salt thereof (e.g., the hydrochloride salt);     -   (ii) a low molecular weight, water-soluble polymer having a         molecular weight of about 40,000 daltons;     -   (iii) a high molecular weight, water-soluble polymer having a         molecular weight from about 140,000 daltons;     -   (iv) a high molecular weight, water-soluble polymer having a         molecular weight from about 370,000 daltons; and     -   (v) a water-soluble polyethylene oxide having a molecular weight         of about 600,000 daltons.

In a particular embodiment of the just-mentioned films, the film components excluding dexmedetomidine or a pharmaceutically acceptable salt thereof form a single layer film substrate, and dexmedetomidine or a pharmaceutically acceptable salt thereof is present on the surface of the film substrate (e.g., within a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, a low molecular weight, water-soluble polymer having a molecular weight of about 40,000 daltons, and a high molecular weight, water-soluble polymer having a molecular weight of about 140,000 daltons). Each water-soluble polymer is, in some embodiments, hydroxypropyl cellulose.

In another embodiment, the oromucosal formulation is a self-supporting, dissolvable, film, comprising:

-   -   (a) a composition consisting essentially of:         -   (i) about 180 μg of dexmedetomidine hydrochloride;         -   (ii) hydroxypropyl cellulose (40,000 MW); and         -   (iii) hydroxypropyl cellulose (140,000 MW); and     -   (b) a film substrate consisting essentially of:         -   (i) hydroxypropyl cellulose (40,000 MW);         -   (ii) hydroxypropyl cellulose (140,000 MW);         -   (iii) hydroxypropyl cellulose (370,000 MW); and         -   (iv) polyethylene oxide (600,000 MW);             wherein the composition of part (a) is present on the             surface of the film substrate (b).

In another embodiment, the oromucosal formulation is a self-supporting, dissolvable, film, comprising:

-   -   (a) a composition consisting essentially of:         -   (i) about 120 μg of dexmedetomidine hydrochloride;         -   (ii) hydroxypropyl cellulose (40,000 MW); and         -   (iii) hydroxypropyl cellulose (140,000 MW); and     -   (b) a film substrate consisting essentially of:         -   (i) hydroxypropyl cellulose (40,000 MW);         -   (ii) hydroxypropyl cellulose (140,000 MW);         -   (iii) hydroxypropyl cellulose (370,000 MW); and         -   (iv) polyethylene oxide (600,000 MW);             wherein the composition of part (a) is present on the             surface of the film substrate (b).

In a particular embodiment of the just-mentioned films, dexmedetomidine hydrochloride is present at about 0.1% to about 2% w/w of the total film weight, hydroxypropyl cellulose (40,000 MW) is present at about 4% to about 8% w/w of the total film weight, hydroxypropyl cellulose (140,000 MW) is present at about 4% to about 8% w/w of the total film weight, hydroxypropyl cellulose (370,000 MW) is present at about 25% to about 30% w/w of the total film weight, and polyethylene oxide (600,000 MW) is present at about 50% to about 60% w/w of the total film weight.

In some embodiments, the present disclosure provides pharmaceutical buccal film compositions comprising or consisting essentially of therapeutically effective amount of dexmedetomidine or pharmaceutically acceptable salt thereof, one or more mucoadhesive polymers and optional excipients selected from one or more of plasticizers, penetration enhancers, coloring agents, sweetening agents, flavoring agents, taste-making agents or salivary stimulants. Mucoadhesive polymers can be selected from hydrophilic polymers and hydrogels. Examples of hydrophilic polymers include polyvinyl alcohol (PVA), sodium carboxy methylcellulose (NaCMC), hydroxyl propyl methyl cellulose (HPMC), hydroxyl ethyl cellulose and hydroxypropyl cellulose (HPC). Examples of hydrogels include anionic polymers like carbopol, polyacrylates, cationic polymers like chitosan and non-ionic polymers like Eudragit analogues.

Sprays, Drops or Gels

In some embodiments, the present disclosure provides pharmaceutical spray compositions or drop compositions suitable for sublingual or buccal administration comprising or consisting essentially of a therapeutically effective amount of dexmedetomidine or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable liquids (from about 1% to about 99.995% by weight). Such liquids can be solvents, co-solvents, or non-solvents for dexmedetomidine or a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, glycerine, N-methylpyrrolidone, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, etc.) or the like. The pharmaceutically acceptable liquid is selected either to dissolve dexmedetomidine or pharmaceutically acceptable salt thereof, to produce a stable, homogenous suspension of it, or to form any combination of a suspension or solution. In addition to these ingredients, spray or drop formulations of dexmedetomidine or pharmaceutically acceptable salt thereof may include one or more excipients such as viscosity modulating materials (e.g., polymers, sugars, sugar alcohols, gums, clays, silicas, and the like, such as polyvinylpyrrolidone (PVP)); preservatives (e.g., ethanol, benzyl alcohol, propylparaben and methylparaben); flavoring agents (e.g., peppermint oil), sweeteners (e.g., sugars such as sucrose, glucose, dextrose, maltose, fructose, etc.), artificial sweeteners (e.g., saccharin, aspartame, acesulfame, sucralose), or sugar alcohols (e.g., mannitol, xylitol, lactitol, maltitol syrup); buffers and pH-adjusting agent (e.g., sodium hydroxide, citrate, and citric acid); coloring agents; fragrances, chelating agents (e.g., EDTA); UV absorbers and antifoam agents (e.g., low molecular weight alcohols, dimethicone). In addition to one or more of the aforementioned ingredients suitable for sublingual or buccal sprays or drops, gel formulations of dexmedetomidine or pharmaceutically acceptable salt thereof may include one or more excipients such as viscosity modulating materials (e.g., water soluble or water swellable polymers such as carbopol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose).

Sprays, drops, and gels can be made by mixing appropriate quantities of the foregoing ingredients in accordance with standard good manufacturing practices. Such excipients can be included in the formulation to improve patient or subject acceptance or taste, to improve bioavailability, to increase shelf-life, to reduce manufacturing and packaging costs, to comply with requirements of governmental regulatory agencies, and for other purposes. The relative amounts of each ingredient should not interfere with the desirable pharmacological and pharmacokinetic properties of the resulting formulation.

In some embodiments, there is provided an oromucosal spray composition comprising or consisting essentially of therapeutically effective amount of dexmedetomidine or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier or excipients.

A patient may, in one embodiment, be treated by administering sublingually or buccally 1 to 2 actuations from a spray pump. An advantage of spray delivery is the ability to easily titrate patients by 1 or 2 doses as required by a single actuation.

Pump action sprays are characterized in requiring the application of external pressure for actuation, for example, external manual, mechanical or electrically initiated pressure. This is in contrast to pressurized systems, e.g., propellant-driven aerosol sprays, where actuation is typically achieved by controlled release of pressure e.g., by controlled opening of a valve.

Various sublingual spray formulations comprising dexmedetomidine hydrochloride at doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg, and 180 μg and excipients as described in Table 1.

TABLE 1 Sublingual spray formulation embodiments according to the disclosure Sublingual Spray Formulation Embodiment No. Ingredients 1 2 3 4 N-methylpyrrolidone ✓ Propylene Glycol ✓ Polyethylene Glycol ✓ Glycerine ✓ Ethanol ✓ ✓ ✓ ✓ Sucralose ✓ ✓ ✓ ✓ Peppermint Oil ✓ ✓ ✓ ✓ Purified water ✓ ✓ ✓ ✓ Optionally other ✓ ✓ ✓ ✓ pharmaceutically acceptable excipients

Various sublingual drop compositions comprising dexmedetomidine hydrochloride at doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg, and 180 μg and excipients as described in Table 2.

TABLE 2 Sublingual drop formulatioms embodiments. Sublingual Drop Formulation Embodiment No. Ingredients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Povidone ✓ ✓ ✓ ✓ ✓ N-methylpyrrolidone ✓ ✓ ✓ Hydroxypropyl ✓ ✓ ✓ ✓ methylcellulose Carbopol ✓ ✓ ✓ ✓ ✓ Polyethylene glycol ✓ ✓ Propylene glycol ✓ ✓ ✓ Glycerine ✓ ✓ ✓ Ethanol ✓ ✓ ✓ Sucralose ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Peppermint Oil ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Purified water ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Optionally other ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ pharmaceutically acceptable excipients

Various sublingual gel compositions comprising dexmedetomidine hydrochloride at doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg and 180 μg and excipients as described in Table 3.

TABLE 3 Sublingual gel formulations embodiments. Sublingual Gel Formulation Embodiment Nos. Ingredients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Carbopol ✓ ✓ ✓ ✓ ✓ Hydroxypropyl ✓ ✓ ✓ ✓ ✓ methylcellulose Hydroxypropyl cellulose Carboxymethyl ✓ ✓ ✓ ✓ ✓ cellulose N- ✓ ✓ ✓ Methylpyrrolidone Propylene glycol ✓ ✓ ✓ Polyethylene glycol ✓ ✓ ✓ Glycerine ✓ ✓ ✓ Ethanol ✓ ✓ ✓ Sucralose ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Peppermint oil ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Purified water ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Optionally other ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ pharmaceutically acceptable excipients

Tablets

In some embodiments, the present disclosure provides tablet formulations suitable for oromucosal administration (e.g., sublingual or buccal administration) comprising or consisting essentially of therapeutically effective amount of dexmedetomidine or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier (from about 1% to about 99.995% by weight). Such carriers can be taste masking agents, diluents, disintegrants, binders, lubricants, glidants, flavouring agents or liquid solvents. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, glycerine, N-methylpyrrolidone, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, etc.) or the like. Taste masking agents include, for example, amberlite, Opadry® AMB TAN, polymethacrylates (especially Eudragi® L100), sodium starch glycolate (Primojel), carbopol polymers, PEG-5M, sodium acetate, ethylcellulose, betacyclodextrin. Flavouring agents can be, for example, mint powder, menthol, vanillin, aspartame, acesulfame potassium, saccharin. Disintegrants include, for example, sodium starch glycolate, low-substituted hydroxy propyl cellulose, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, guar gum, methylcellulose, polacrilin potassium, poloxamer, sodium alginate. Diluents can be, for example, microcrystalline cellulose, dextrates, dextrose, fructose, mannitol, sucralose, sorbitol, starch, pregelatinized starch, sucrose, xylitol, maltose, maltodextrin, maltitol. Binders can be, for example, alginic acid, carbomer, ethyl cellulose, gelatine, liquid glucose, guar gum, hydroxyethyl cellulose, methylcellulose, polydextrose, polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate. At least one lubricant may conveniently be incorporated into the formulation to prevent the powder from adhering to tablet punches during the compression procedure. Lubricants can be, for example, talc, magnesium stearate, calcium stearate, glyceryl behenate, hydrogenated castor oil, stearic acid, sodium lauryl sulphate. Glidants are used to promote powder flow by reducing interparticle friction and cohesion. These are used in combination with lubricants as they have no ability to reduce die wall friction. Glidants, can be, for example, colloidal silicon dioxide, calcium silicate, calcium phosphate tribasic.

Various buccal tablet formulations comprising dexmedetomidine hydrochloride at doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg and 180 μg and excipients as described in Table 4.

TABLE 4 Buccal tablet formulation embodiments. Buccal Tablet Formulation Embodiment No. Ingredients 1 2 3 4 5 Lactose monohydrate ✓ ✓ ✓ ✓ ✓ Polyethylene oxide ✓ Hydroxypropyl ✓ cellulose Hydroxypropyl ✓ methylcellulose Sodium alginate ✓ Xanthan gum ✓ Sucralose ✓ ✓ ✓ ✓ ✓ Magnesium stearate ✓ ✓ ✓ ✓ ✓ Talc ✓ ✓ ✓ ✓ Optionally other ✓ ✓ ✓ ✓ ✓ pharmaceutically acceptable excipients

Various sublingual tablet compositions comprising dexmedetomidine hydrochloride at doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg, and 180 μg and excipients as described in Table 5.

TABLE 5 Sublingual Tablet Formulation Embodiment No. Ingredients 1 2 3 4 5 6 7 8 9 10 Lactose Monohydrate ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Hydroxypropyl ✓ ✓ methylcellulose Hydroxypropyl cellulose ✓ ✓ Croscarmellose Sodium ✓ ✓ ✓ ✓ ✓ Sodium starch glycolate ✓ ✓ ✓ ✓ ✓ Polyethylene oxide ✓ ✓ Xanthan gum ✓ ✓ Sodium alginate ✓ ✓ Sucralose ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Magnesium stearate ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Optionally other ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ pharmaceutically acceptable excipients Methods and Administration

The disclosed invention is related to the discovery that dexmedetomidine clearance was decreased in human subjects with a hepatic impairment, e.g., an impairment classified as Child-Pugh Class A, B, or C. Accordingly, such subjects can be treated with a reduced dose of an oromucosal formulation comprising dexmedetomidine or a pharmaceutically acceptable salt thereof compared to a human subject with normal hepatic function.

Accordingly, the disclosed invention provides a method of using dexmedetomidine, comprising:

-   -   administering an initial dose of dexmedetomidine or a         pharmaceutically acceptable salt thereof in an oromucosal         formulation to a human subject having an agitation associated         with schizophrenia or bipolar I or II disorder;     -   optionally administering a second dose of dexmedetomidine or the         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject at least two hours after and         within 24 hours of the initial dose; and     -   optionally administering a third dose of dexmedetomidine or the         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject at least two hours after the         second dose and within 24 hours of the initial dose;     -   wherein the administration of the dexmedetomidine does not         exceed a maximum total daily dosage;     -   wherein the human subject has a hepatic impairment;     -   wherein the second dose and the third dose are 60 mcg of         dexmedetomidine each;     -   wherein the initial dose is 90 mcg of dexmedetomidine and the         maximum total daily dosage is 210 mcg of dexmedetomidine if the         agitation is mild or moderate, and the hepatic impairment is         mild or moderate;     -   wherein the initial dose is 120 mcg of dexmedetomidine and the         maximum total daily dosage is 240 mcg of dexmedetomidine if the         agitation is severe, and the hepatic impairment is mild or         moderate;     -   wherein the initial dose is 60 mcg of dexmedetomidine and the         maximum total daily dosage is 180 mcg of dexmedetomidine if the         agitation is mild or moderate and the hepatic impairment is         severe; and     -   wherein the initial dose is 90 mcg of dexmedetomidine and the         maximum total daily dosage is 210 mcg of dexmedetomidine if the         agitation is severe and the hepatic impairment is severe.

The Positive and Negative Syndrome Scale-Excited Component (PEC) is an investigator-rated instrument that can be used to measure the degree of agitation. The PEC score consists of 5 items: poor impulse control, tension, hostility, uncooperativeness, and excitement. Each item is scored on a scale from 1 to 7 (1=absent, 2=minimal, 3=mild, 4=moderate, 5=moderate-severe, 6=severe, 7=extremely severe). The total PEC score ranges from 5 to 35, with higher scores reflecting greater overall symptom severity.

In some embodiments of the method, agitation that is mild or moderate is defined as a PEC score of 19 or lower (e.g., a score of 5 to 19, including scores of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19). In some embodiments of the method, agitation that is mild is defined as a PEC score of 13 or lower (e.g., a score of 5 to 13, including scores of 5, 6, 7, 8, 9, 10, 11, 12, or 13). In some embodiments of the method, agitation that is moderate is defined as a PEC score of 14 to 19 inclusive (e.g., 14, 15, 16, 17, 18, or 19). In some embodiments of the method, agitation that is severe is defined as a PEC score of 20 or higher (e.g., a score of 20 to 35, including 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35).

The Child-Pugh classification for measuring the severity of hepatic impairment (e.g., liver disease) typically is measured based on the degree of ascites, the serum concentrations of bilirubin and albumin, the prothrombin time, and the degree of encephalopathy. A point is assigned based on criterion based on increasing severity.

Encephalopathy: None=1 point, Grade 1 and 2=2 points, Grade 3 and 4=3 points

Ascites: None=1 point, slight=2 points, moderate=3 points

Bilirubin: under 2 mg/ml=1 point, 2 to 3 mg/ml=2 points, over 3 mg/ml=3 points

Albumin: greater than 3.5 mg/ml=1 point, 2.8 to 3.5 mg/ml=2 points, less than 2.8 mg/ml=3 points

Prothrombin Time (sec prolonged): less than 4 sec=1 point, 4 to 6 sec=2 points, over 6 sec=3 points

Frequently the international normalized ratio (INR) will be used as a substitute for prothrombin time, with INR under 1.7=1 point, INR 1.7 to 2.2=2 points, INR above 2.2=3 points.

Typically, Child-Pugh Class A is 5 to 6 points, Child-Pugh Class B is 7 to 9 points (i.e., 7, 8, or 9 points), and Child-Pugh Class C is 10 to 15 points (i.e., 10, 11, 12, 13, 14, or 15 points).

In some embodiments of the method, the hepatic impairment is mild that is defined as Child-Pugh Class A. In some embodiments of the method, the hepatic impairment is moderate that is defined as Child-Pugh Class B. In some embodiments of the method, the hepatic impairment is severe that is defined as Child-Pugh Class C.

In some embodiments of the method, only a first dose is required and second and third doses are not needed. In some embodiments of the method, only a first and second dose are required and a third dose is not needed. In other embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In some embodiments of the method, the agitation is mild or moderate and the hepatic impairment is mild or moderate, and wherein the initial dose is 90 mcg of dexmedetomidine and the maximum total daily dosage is 210 mcg of dexmedetomidine. In some embodiments of the method, the second dose is administered at least two hours after the initial dose and within 24 hours of the initial dose. In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In some embodiments of the method, the agitation is severe and the hepatic impairment is mild or moderate, and wherein the initial dose is 120 mcg of dexmedetomidine and the maximum total daily dosage is 240 mcg of dexmedetomidine. In some embodiments of the method, the second dose is administered at least two hours after the initial dose and within 24 hours of the initial dose. In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In some embodiments of the method, the agitation is mild or moderate and the hepatic impairment is severe, and wherein the initial dose is 60 mcg of dexmedetomidine and the maximum total daily dosage is 180 mcg of dexmedetomidine. In some embodiments of the method, the second dose is administered at least two hours after the initial dose and within 24 hours of the initial dose. In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In some embodiments of the method, the agitation is severe and the hepatic impairment is severe, and wherein the initial dose is 90 mcg of dexmedetomidine and the maximum total daily dosage is 210 mcg of dexmedetomidine. In some embodiments of the method, the second dose is administered at least two hours after the initial dose and within 24 hours of the initial dose. In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

The disclosed invention further provides a method of using an oromucosal formulation of dexmedetomidine for an acute treatment of an agitation associated with schizophrenia or bipolar I or II disorder in a human subject, wherein the human subject does not have a hepatic impairment, the method comprising:

-   -   administering an initial dose of dexmedetomidine or a         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject;     -   optionally administering a second dose of dexmedetomidine or the         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject at least two hours after and         within 24 hours of the initial dose; and     -   optionally administering a third dose of dexmedetomidine or the         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject at least two hours after the         second dose and within 24 hours of the initial dose;     -   wherein the administration of the dexmedetomidine does not         exceed a maximum total daily dosage;     -   wherein the initial dose, the second dose, the third dose, and         the maximum total daily dosage are 120 mcg, 60 mcg, 60 mcg, and         240 mcg of dexmedetomidine, respectively, if the human subject         is younger than 65 years of age and if the agitation is mild or         moderate;     -   wherein the initial dose, the second dose, the third dose, and         the maximum total daily dosage are 180 mcg, 90 mcg, 90 mcg, and         360 mcg of dexmedetomidine, respectively, if the human subject         is younger than 65 years of age and if the agitation is severe;         and     -   wherein the initial dose, the second dose, the third dose, and         the maximum total daily dosage are 120 mcg, 60 mcg, 60 mcg, and         240 mcg of dexmedetomidine, respectively, if the human subject         is 65 years of age or older and if the agitation is mild,         moderate, or severe.

In some embodiments of the method, only a first dose is required and second and third doses are not needed. In some embodiments of the method, only a first and second dose are required and a third dose is not needed. In other embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In some embodiments of this method, the human subject is younger than 65 years of age and the agitation is mild or moderate, and wherein the initial dose, the second dose, the third dose, and the maximum total daily dosage are 120 mcg, 60 mcg, 60 mcg, and 240 mcg of dexmedetomidine, respectively. In some embodiments of the method, the second dose is administered at least two hours after the initial dose and within 24 hours of the initial dose. In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In some embodiments of this method, the human subject is younger than 65 years of age and the agitation is severe, and wherein the initial dose, the second dose, the third dose, and the maximum total daily dosage are 180 mcg, 90 mcg, 90 mcg, and 360 mcg of dexmedetomidine, respectively. In some embodiments of the method, the second dose is administered at least two hours after the initial dose and within 24 hours of the initial dose. In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In some embodiments of this method, the human subject is 65 years of age or older and the agitation is mild, moderate, or severe, and wherein the initial dose, the second dose, the third dose, and the maximum total daily dosage are 120 mcg, 60 mcg, 60 mcg, and 240 mcg of dexmedetomidine, respectively. In some embodiments of the method, the second dose is administered at least two hours after the initial dose and within 24 hours of the initial dose. In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

The disclosed invention further provides a method of using an oromucosal formulation of dexmedetomidine for an acute treatment of an agitation associated with schizophrenia or bipolar I or II disorder in a human subject, the method comprising:

-   -   administering an initial dose of dexmedetomidine or a         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject;     -   optionally administering a second dose of dexmedetomidine or the         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject at least two hours after and         within 24 hours of the initial dose; and     -   optionally administering a third dose of dexmedetomidine or the         pharmaceutically acceptable salt thereof in the oromucosal         formulation to the human subject at least two hours after the         second dose and within 24 hours of the initial dose;     -   wherein the administration of the dexmedetomidine does not         exceed a maximum total daily dosage;     -   wherein the initial dose, the second dose, the third dose, and         the maximum total daily dosage are 120 mcg, 60 mcg, 60 mcg, and         240 mcg of dexmedetomidine, respectively, if the human subject         is younger than 65 years of age and if the agitation is mild or         moderate;     -   wherein the initial dose, the second dose, the third dose, and         the maximum total daily dosage are 180 mcg, 90 mcg, 90 mcg, and         360 mcg of dexmedetomidine, respectively, if the human subject         is younger than 65 years of age and if the agitation is severe;         and     -   wherein the initial dose, the second dose, the third dose, and         the maximum total daily dosage are 120 mcg, 60 mcg, 60 mcg, and         240 mcg of dexmedetomidine, respectively, if the human subject         is 65 years of age or older and if the agitation is mild,         moderate, or severe.

In some embodiments of the method, only a first dose is required and second and third doses are not needed. In some embodiments of the method, only a first and second dose are required and a third dose is not needed. In other embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In some embodiments of this method, the human subject is younger than 65 years of age and the agitation is mild or moderate, and wherein the initial dose, the second dose, the third dose, and the maximum total daily dosage are 120 mcg, 60 mcg, 60 mcg, and 240 mcg of dexmedetomidine, respectively. In some embodiments of the method, the second dose is administered at least two hours after the initial dose and within 24 hours of the initial dose. In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In some embodiments of this method, the human subject is younger than 65 years of age and the agitation is severe, and wherein the initial dose, the second dose, the third dose, and the maximum total daily dosage are 180 mcg, 90 mcg, 90 mcg, and 360 mcg of dexmedetomidine, respectively. In some embodiments of the method, the second dose is administered at least two hours after the initial dose and within 24 hours of the initial dose. In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In some embodiments of this method, the human subject is 65 years of age or older and the agitation is mild, moderate, or severe, and wherein the initial dose, the second dose, the third dose, and the maximum total daily dosage are 120 mcg, 60 mcg, 60 mcg, and 240 mcg of dexmedetomidine, respectively. In some embodiments of the method, the second dose is administered at least two hours after the initial dose and within 24 hours of the initial dose. In some embodiments of the method, the third dose is administered at least two hours after the second dose and within 24 hours of the initial dose.

In any embodiments of the method, the oromucosal formulation further comprises at least one water-soluble polymer. In some embodiments, the at least one water-soluble polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxy methylcellulose, methylcellulose, polyethylene oxide (PEO), and mixtures thereof. In some embodiments, the at least one water-soluble polymer is hydroxypropyl cellulose.

In some embodiments, the treatment is effective without causing significant sedation. In some embodiments, the condition is agitation or signs of agitation. In some embodiments, the agitation or signs of agitation are associated with schizophrenia. In some embodiments, the agitation or signs of agitation are associated with a bipolar illness such as bipolar I disorder or bipolar II disorder.

In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects. In some embodiments, agitation or signs of agitation is treated without the subject's diastolic blood pressure falling below about 60 mmHg and/or without the subject's heart rate falling below about 50 beats per minute. In some embodiments, agitation or signs of agitation is treated without the subject's systolic blood pressure falling below about 80 mmHg and or/without the subject's diastolic blood pressure falling below about 60 mmHg and/or without the subject's heart rate falling below about 50 beats per minute.

In some embodiments, the present disclosure provides a method of treating acute agitation associated with schizophrenia and bipolar disorder (e.g., bipolar I disorder or bipolar II disorder) in a human subject, comprising oromucosally administering a film composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride salt) as a single dose of 120 μg or 180 μg. In some embodiments, an additional dose (e.g., 90 μg or 60 μg) can be taken after a suitable period of time (e.g., after about 2 hours) in the event of persistent or recurrent agitation (e.g., by cutting a 180 μg or 120 μg film in half).

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by the sublingual or buccal route. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a tablet, film, spray, gel or drops, particularly a film. In some embodiments, the film is placed under the tongue, close to the base of the tongue, on the left or right side. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally in the form of a film, patch or tablet, particularly a film. In some embodiments, the film is placed against the inner lip or check, close to the jaw line.

In some embodiments, the oromucosal formulation is a self-supporting, dissolvable, film comprising:

-   -   (a) a composition comprising or consisting essentially of:     -   (i) about 180 μg of dexmedetomidine hydrochloride;     -   (ii) hydroxypropyl cellulose (40,000 MW); and     -   (iii) hydroxypropyl cellulose (140,000 MW); and     -   (b) a film substrate comprising or consisting essentially of:     -   (i) hydroxypropyl cellulose (40,000 MW);     -   (ii) hydroxypropyl cellulose (140,000 MW);     -   (iii) hydroxypropyl cellulose (370,000 MW); and     -   (iv) polyethylene oxide (600,000 MW);         wherein the composition of part (a) is present on the surface of         the film substrate (b).

In some embodiments, the oromucosal formulation is a self-supporting, dissolvable, film comprising:

(a) a composition comprising or consisting essentially of:

-   -   (i) about 120 μg of dexmedetomidine hydrochloride;     -   (ii) hydroxypropyl cellulose (40,000 MW); and     -   (iii) hydroxypropyl cellulose (140,000 MW); and     -   (b) a film substrate comprising or consisting essentially of:     -   (i) hydroxypropyl cellulose (40,000 MW);     -   (ii) hydroxypropyl cellulose (140,000 MW);     -   (iii) hydroxypropyl cellulose (370,000 MW); and     -   (iv) polyethylene oxide (600,000 MW);         wherein the composition of part (a) is present on the surface of         the film substrate (b).

In some embodiments, agitation or signs of agitation are significantly reduced within 60 minutes in a patient with schizophrenia or bipolar disorder following administration of the initial dose, optional second dose, and optional third dose of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride), as measured by the relative PEC scores just prior to and 60 minutes after administering dexmedetomidine or a pharmaceutically acceptable salt thereof.

In some embodiments, the relative PEC scores are different by at least six points. In another embodiment, the relative PEC scores are different by at least eight points. In yet another embodiment, the difference in relative PEC scores is maintained for at least six hours. In a particular embodiment, a difference of at least eight points is maintained for up to about 24 hours when administering the initial dose, optional second dose, and optional third dose of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride).

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered immediately prior to or immediately following the appearance of agitation or signs of agitation in the human subject.

In some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (e.g., bipolar I disorder or bipolar II disorder), and in some embodiments, the patient has both schizophrenia and bipolar disorder (e.g., bipolar I disorder or bipolar II disorder).

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 10 minutes following the appearance of agitation or signs of agitation in the human subject. In some embodiments, an additional dose of 60 μg and an optional third dose can be taken after a suitable period of time (e.g., two hours or more within a 24 hour time period starting from the initial dose) of prior dose. For example, the period of time can be about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, or about 23 hours. In some embodiments, the second dose is administered after a period of about 2 hours.

In accordance with some embodiments of the methods of treating agitation comprising administering the oromucosal formulation to a patient in the fasted state. In some embodiments, the oromucosoal formulation can be administered in the fed state.

In some embodiments of the methods, agitation is significantly reduced within about 2 hours of administering the composition, as measured by a mean change in Positive and Negative Syndrome Scale Excited Component (PEC) scores relative to baseline. In some embodiments, the agitation is significantly reduced within about 45 minutes to about 1 hour. In some embodiments, the agitation is significantly reduced in less than 45 minutes (e.g., about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes). In some embodiments, the patient experiences ≥40% decrease from baseline in PEC score. For example, the human subject may experience greater than or equal to about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, or about 150% from baseline. Treatment efficacy may also be compared by comparing PEC score to placebo. In some embodiments, the PEC score is ≥30% lower than placebo (e.g., the placebo group has mean change from baseline in PEC total score of −3 and the dexmedetomidine-containing composition has a score of −3.9). For example, compared to placebo, the patient's PEC score can be lower by greater than or equal to about 30,%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, or about 200%. In some embodiments, the patient experiences a mean change in PEC score of greater than about −4 (i.e. a decrease of 4 or more points) relative to baseline within 2 hours of administering the composition. For example, at the 2 hour time point, the patient may experience a mean change in PEC score of greater than about −4, about −5, about −6, about −7, about −8, about −9, about −10, about −11, or about −12. In some embodiments, the decrease in PEC score (e.g., of greater than about −4) is maintained for at least six hours following administration of the composition. For example, if a patient experiences a mean change from baseline in PEC total score of e.g., −6 at 2 hours, then at 6 hours patient's mean change in PEC score will be about −6 or lower (e.g., −7, −8, etc.). In some embodiments, the decrease in PEC score (e.g., of greater than about −4) is substantially maintained for at least six hours following administration of the composition. For example, if a patient experiences a mean change from baseline in PEC total score of e.g., −6 at 2 hours, then at 6 hours patient's mean change in PEC score will be about −4, about −5, or about −6 or lower (e.g., −7, −8, etc.). In some embodiments, the mean change in PEC score is greater than or equal to −8 and is maintained from 2 hours post administration up to at least about 6 hours following administration of the composition.

In some embodiments, the composition is administered twice daily. In some embodiments, the composition comprises a dose range of dexmedetomidine or a pharmaceutically acceptable salt thereof of between about 30 μg and about 240 μg. For example, the composition comprises a unit dose of about 30 μg, about 60 μg, about 90 μg, about 120 μg, or 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, a single dose of a composition comprising about 60 μg, about 90 μg, or about 120 μg dexmedetomidine or a pharmaceutically acceptable salt thereof is effective for up to at least about 24 hours. In some embodiments, the composition is administered twice daily for 7 days.

In some embodiments, the present disclosure provides methods of reducing agitation to a 1 (very much improved) or 2 (much improved) within 2 hours of administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride), as measured by the Clinical Global Impression-Improvement Scale. In some embodiments, the agitation is reduced within about 30 minutes to about 1 hour. In some embodiments, the reduction in agitation is maintained for greater than about 2 hours. For example, the reduction in agitation is maintained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23, or about 24 hours. In some embodiments, the composition comprises about 120 μg of dexmedetomidine. In some embodiments, the composition comprises about 180 μg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar disorder.

In some embodiments, the present disclosure provides methods of reducing agitation to a 3 (mild agitation) or 4 (normal behavior) within 2 hours of administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by the Agitation-Calmness Evaluation Scale (ACES). In some embodiments, the agitation is reduced within about 30 minutes to about 1 hour. In some embodiments, the reduction in agitation is reduced to a 4 (normal behavior). In some embodiments, the reduction in agitation is maintained for greater than about 2 hours. For example, the reduction in agitation is maintained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the composition comprises about 120 μg of dexmedetomidine. In some embodiments, the composition comprises about 180 μg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar disorder.

In some embodiments, the present disclosure provides methods of achieving a ≥40% reduction in agitation, within 2 hours of administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by the PEC scale. In some embodiments, the agitation is reduced within about 30 minutes to about 1 hour. In some embodiments, the reduction in agitation ≥40%, ≥50%, ≥60%, ≥70%, ≥80%, ≥90%, or ≥100%. In some embodiments, the reduction in agitation is maintained for greater than about 2 hours. For example, the reduction in agitation is maintained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the composition comprises about 60 μg, about 90 μg, or about 120 μg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar I or II disorder. In some embodiments, the patient has both schizophrenia and either bipolar I or II disorder.

In some embodiments, the present disclosure provides a method of achieving a PEC score reduction in agitation for a sustained period of time in a subject with bipolar or schizophrenic subject comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 60 μg, about 90 μg, or about 120 μgm, wherein the PEC score reduction is about −8 to about −10 and wherein the sustained period is about 2 hours to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, the sustained period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the PEC score reduction is about −8, about −9, or about −10.

In some embodiments, the present disclosure provides a method of achieving an ACES score improvement for a sustained period of time in a subject with bipolar or schizophrenic subject comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 60 μg, about 90 μg, or about 120 μg, wherein the ACES score is improved to about 3 to about 4 and wherein the sustained period is about 2 hours to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride in an amount equivalent to provide about 60 μg, about 90 μg, or about 120 μg of dexmedetomidine. In some embodiments, the sustained period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the ACES score is about 4.

In some embodiments, the present disclosure provides a method of achieving an CGI-I score improvement for a sustained period of time in a subject with bipolar or schizophrenic subject comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 60 μg, about 90 μg, or about 120 μg, wherein the CGI-I score is improved to about a 1 (very much improved) or about a 2 (much improved) and wherein the sustained period is about 2 hours to about 6 hours. In some embodiments, the oromucosal formulation comprises dexmedetomidine hydrochloride in an amount equivalent to provide about 60 μg, about 90 μg, or about 120 μg of dexmedetomidine. In some embodiments, the sustained period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the CGI-I score is about 1.

EXAMPLES

The example presented below is provided for the purpose of illustration only and the embodiments described herein should in no way be construed as being limited to this example. Rather, the embodiments should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

Example 1: Dexmedetomidine Sublingual Film Formulation

TABLE 6 Dexmedetomidine deposited on the surface of a polymer matrix film composition Concen- Concen- tration tration g/100 g g/100 g (10 μg (20 μg Ingredients film) film) Function Drug-containing composition Dexmedetomidine 0.136 0.267 Active agent hydrochloride Hydroxypropyl cellulose, 0.301 0.593 Film former HPC-SSL (MW = 40,000) Hydroxypropyl cellulose 0.301 0.593 Film former (MW = 140,000) FD&C Blue #1 Granular 0.002 0.004 Color Ethyl Alcohol as a solvent qs qs Solvent Polymer matrix composition Hydroxypropyl cellulose 4.803 4.768 Film former (MW = 140,000) Hydroxypropyl cellulose, 4.803 4.768 Film former HPC-SSL (MW = 40,000) Hydroxypropyl cellulose 28.809 28.601 Film former (MW = 370,000) Fast Emerald Green Shade 0.129 0.128 Color (NO. 06507) Sucralose, USP-NF Grade 0.993 0.985 Sweetener Peppermint Oil, NF 2.104 2.089 Flavor Polyethylene oxide 57.618 57.202 Film former & (Sentry Polyox WSR 205 Mucoadhesive LEO NF) (MW = 600,000) Water as a solvent qs qs Solvent

(A) Process for the Preparation of Polymer Matrix:

Polymer mixture: Polyethylene oxide and fast emerald green shade were mixed in water for at least 180 minutes at about 1400 rpm to about 2000 rpm. Sucralose, hydroxypropyl cellulose (molecular weight 140K), hydroxypropyl cellulose, HPC-SSL (molecular weight 40K) and hydroxypropyl cellulose (molecular weight 370K) were added and mixed for at least 120 minutes at about 1600 rpm to 2000 rpm. Peppermint Oil was added to water and the resultant dispersion was then added to the polymer mixture and mixed for at least 30 minutes. The resultant mixture was further mixed under vacuum (248 torr) for at least for 30 minutes at a speed of 350 rpm and at temperature of 22.9° C.

Coating station: A roll was placed on an unwind stand and the leading edge was thread through guide bars and coating bars. The silicone-coated side of the liner was placed faced up. A gap of 40 millimeters was maintained between the coating bars. The oven set point was adjusted to 70° C. and the final drying temperature was adjusted to 85° C.

Coating/drying process: The polymer mixture was poured onto the liner between the guide bars and the coating bars. The liner was pulled slowly through the coating bar at a constant speed by hand until no liquid was remained on the coating bars. The liner was cut to approximately 12-inch length hand sheets using a safety knife. Each hand sheet was placed on a drying board and was tapped on the corners to prevent curl during drying. The hand sheets were dried in the oven until the moisture content was less than 5% (approximately 30 minutes) and then removed from the drying board. The coating weights were checked against the acceptance criteria, and if met, the hand sheets were then stacked and placed in a 34 inch×40 inch foil bag that was lined with PET release liner.

(B) Process for the Preparation of Deposition Solution:

FDC blue was dissolved in ethyl alcohol for at least 180 minutes. Dexmedetomidine hydrochloride was added to the ethyl alcohol solution with continuous stirring for 10 minutes at about 400 rpm to about 800 rpm. Hydroxypropyl cellulose (40K) and hydroxypropyl cellulose (140K) were added to the mixture, and stirred for at least 30 minutes until all the materials were dissolved.

(C) Process for the Preparation of Micro-Deposited Matrix:

The deposition solution obtained in Step (B) above was filled into a pipette to the required volume (determined according to the specific drug product strength of the final product). An appropriate amount (1.5 microliters=approximately 5 μg) of the deposition solution were deposited (e.g., as droplets) onto the polymer matrix obtained in Step (A), and repeated to a total of 10 times (i.e. 10 deposits/droplets) with space between each deposit to prevent merging of the deposits/droplets and allow subsequent cutting of the film into individual drug-containing units. The film was initially die cut in individual units with dimensions of 22 mm×8.8 mm containing a single deposit of the drug-containing composition. The die cut micro-deposited matrixes were then dried in an oven for 70° C. for 10 minutes and further die cut into 10 units with each unit containing a single deposit of the drug-containing composition.

(D) Packaging:

Each defect-free unit was sealed individually into a foil pouch, which was then heat sealed. If the heat seal was acceptable the package was considered as an acceptable unit for commercial use.

Other unit strengths (e.g., 40 μg and 60 μg films) were similarly prepared by varying the concentrations of drug, polymers and colorant within the drug-containing composition. For example, the 40 μg and 60 μg, films were prepared from drug-containing compositions containing, respectively, approximately 2× and 3×, the amounts of drug, polymers and colorant that appear in the 20 μg drug-containing composition described in table 6 above.

Example 2:

TABLE 7 Dexmedetomidine deposited on the surface of a polymer matrix film composition Concen- Concen- Concen- tration tration tration mg/unit mg/unit mg/unit (80 μg (120 μg (180 μg Ingredients film) film) film) Function Drug-containing composition Dexmedetomidine 0.0945 0.142 0.213 Active agent hydrochloride Hydroxypropyl 0.0812 0.122 0.183 Film former cellulose, HPC-SSL (MW = 40,000) Hydroxypropyl cellulose 0.0812 0.122 0.183 Film former (MW = 140,000) FD&C Blue #1 Granular 0.0008 0.001 0.002 Color Ethyl Alcohol as a q.s q.s. q.s. Solvent solvent Polymer matrix composition Hydroxypropyl cellulose 0.627  0.627 0.627 Film former (MW = 140,000) Hydroxypropyl 0.627  0.627 0.627 Film former cellulose, HPC-SSL (MW = 40,000) Hydroxypropyl cellulose 3.763  3.763 3.763 Film former (MW = 370,000) Fast Emerald Green 0.017  0.017 0.017 Color Shade (NO. 06507) Sucralose, USP-NF 0.130  0.130 0.130 Sweetener Grade Peppermint Oil, NF 0.275  0.275 0.275 Flavor Polyethylene oxide 7.526  7.526 7.526 Film former & (Sentry Polyox WSR Mucoadhesive 205 LEO NF) (MW = 600,000) Water as a solvent qs qs qs Solvent

The formulations (80 μg, 120 μg and 180 μg) in Table 7 were prepared using the same manufacturing process as described above in Example 1.

Example 3: A Phase Ib Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study to Determine Efficacy, Pharmacokinetics and Safety of Dexmedetomidine Hydrochloride Sublingual Film in Treating Agitation Associated with Schizophrenia

Primary Objective:

To determine the doses of dexmedetomidine hydrochloride sublingual film needed to effectively reduce symptoms of acute agitation associated with schizophrenia, schizoaffective disorder or schizophreniform disorder assessed using the Positive and Negative Syndrome Scale—Excited Component (PEC) change from baseline after drug treatment.

Secondary Objective:

Determine PK, safety and tolerability of the various film strengths of dexmedetomidine hydrochloride sublingual film in patients with acute agitation associated with schizophrenia, schizoaffective disorder or schizophreniform disorder.

-   -   1. Describe overall clinical improvement after drug         administration by Clinical Global Impression-Improvement scale         (CGI-I).     -   2. Describe the duration of calming effect as measured by PEC         and ACES.     -   3. Determine the safety profile of dexmedetomidine hydrochloride         sublingual film as measured by vital signs and reports of         adverse events.     -   4. Describe the overall tolerability in terms of adverse event         reports and local site (oral/sublingual) tolerability of the         sublingual film.     -   5. Describe the pharmacokinetics of dexmedetomidine         hydrochloride sublingual film in the patient population.     -   6. Visual Analog Scales (VAS) to capture subject's opinion on         taste and acceptability as well as questions regarding         likability of study medication.

Methodology: This was a two-stage adaptive Phase Ib trial design. It was a randomized, double-blind, placebo-controlled, multiple ascending dose study assessing efficacy, pharmacokinetics, safety and tolerability of dexmedetomidine hydrochloride sublingual film dosing in adult (18-65 years old) males and females with acute agitation associated with schizophrenia, schizoaffective disorder, or schizophreniform disorder.

The first stage was designed to characterize a safe and tolerable dose range which produced a calming effect as measured using the PEC total score. The second stage was designed to enroll a total of 40 subjects per dose group in a three-arm placebo-controlled design to better characterize the broader range of safety and tolerability as well as better estimate variability (effect size).

Adaptive evaluation of escalating dose regimens of 20 μg, 60 μg and 120 μg were performed for the first stage, with an option to test a different dose should a safety or tolerability signal be observed. Male and female adults with acute agitation associated with schizophrenia, schizoaffective disorder, or schizophreniform disorder were enrolled in each cohort. Investigators were permitted to repeat dosing 1 hour after administration if there was a lack of significant efficacy (PEC change from baseline ≤40%) (maximum number of doses per subject was 2) and in the absence of safety concerns.

Blinded periodic safety data reviews were undertaken after completion of dosing each cohort to review all safety data as it became available. Dose escalation was allowed unless a safety or tolerability issue became evident upon periodic regular safety reviews. Based upon blinded analyses of the safety and tolerability of all subject cohorts, additional doses were selected.

Eligible subjects (acutely agitated subjects with schizophrenia, schizoaffective, or schizophreniform disorder) were identified in outpatient clinics, mental health, psychiatric or medical emergency services including medical/psychiatric observation units, or as newly admitted to a hospital setting for acute agitation or already in hospital for chronic underlying conditions. Subjects were domiciled in a clinical research setting or hospitalized to remain under medical supervision while undergoing screening procedures to assess eligibility.

Upon confirmation of eligibility, subjects were randomized to dexmedetomidine hydrochloride sublingual film or placebo film. At the beginning of each study session, a single dose of dexmedetomidine hydrochloride sublingual film was self-administered sublingually, after training with a placebo film and under the supervision of an unblinded staff who did not participate in evaluation of safety or efficacy. The drug film was retained in the sublingual (SL) cavity until dissolved. Participants were also evaluated for local irritation around the area where the film was placed. Efficacy and safety assessments were conducted periodically before and after dosing. If reduction in PEC was less than or equal to 40% one hour after the first administration, the investigator could administer a second dose of dexmedetomidine hydrochloride sublingual film (of the same randomized dose) with an additional PEC assessment completed at 1.5 hr post-dose. All efforts were made to have the patient perform all assessments as per protocol. However, should the patient's situation warrant it, standard of care treatment was initiated, e.g., after the 4 hr assessments were completed. In Stage 1 each cohort included 27 subjects randomized 2:1 to dexmedetomidine hydrochloride sublingual film or placebo film (i.e., 18 received dexmedetomidine hydrochloride sublingual film and 9 received placebo film). Three doses were initially planned (total of 81 subjects). Per protocol, different or additional doses could be tested based on ongoing safety reviews, and two additional dose levels were tested: 80 μg and 180 μg (Table 8).

Efficacy Assessments:

The efficacy of dexmedetomidine hydrochloride sublingual film on reducing acute agitation was assessed using the Positive and Negative Syndrome Scale—Excited Component (PEC) scale which was performed at screening, baseline (i.e., also referred to as pre-dose) and at 10, 20, 30, 45 min; 1, 1.5, 2, 4, 6, and 24 hours post the first dose.

-   -   Overall agitation and sedation were evaluated with the         Agitation-Calmness Evaluation Scale (ACES), which was performed         at baseline (pre-dose) and at 2 and 4 hours post-first dose.     -   The change in agitation in response to treatment was also         measured by the Clinical Global Impressions-Improvement (CGI-I),         performed at 1, 2 and 4 hours post the first dose.

Safety and Tolerability Assessments:

AEs, clinical laboratory tests, electrocardiogram (ECG) with rhythm strip, and vital signs were monitored for tolerability assessment. All observed and volunteered AEs were recorded. The relationship of AEs to the study drugs was graded as not related, unlikely/remotely related, possibly related, probably related or definitely related by the investigators.

Resting vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate, as well as ECG were measured at prior to the PK assessments. Resting vital signs (SBP, DBP and HR) were taken at screening, baseline (pre-dose) and at 30 min, 1, 2, 4 and 8 hours post-first dose. Orthostatic measurements which included (SBP, DBP, HR, respiratory rate and temperature) were taken at screening, pre-dose, 2, 4 and 24 hours post-first dose. ECGs were conducted at screening, baseline (pre-dose), 2 and 24 hours post-first dose. The application site of the SL preparation (buccal mucosa) were also inspected for any signs of local irritation.

Safety and tolerability assessments were continued until the morning of Day 3 (day of discharge) and were repeated on Day 7(+2). AEs evaluation were conducted at screening, baseline (pre-dose), 2 hours, Day 3 and Day 7(+2) post—the first dose. Safety Labs including chemistry, hematology, urinalysis, UDS, alcohol breathalyzer, and urine pregnancy were performed at screening, Day 3 and Day 7(+2).

Any abnormal vital sign measurement, clinical laboratory test, physical examination finding, or ECG parameter deemed clinically significant by the investigator was repeated, including test results obtained on the final study day or upon early termination. For any test abnormality deemed clinically significant, repeat analysis was performed during the follow-up period and until the value returned to baseline (or within normal limits) or the investigator deemed the abnormality to be stable and no longer of clinical concern.

Three analysis populations were defined for the study:

Safety Population: All subjects who receive study drug

Intent to treat (ITT) Population: All subjects in the Safety Population who have a PEC Score

Per Protocol (PP) Population: All subjects in the ITT Population with no major protocol deviations

Subjects were on a range of typically prescribed antipsychotics.

TABLE 8 Arms and Interventions Arms Intervention Placebo Comparator: Placebo Drug: Placebo film Sublingual Film with no active Placebo film for dexmedetomidine drug; single administration hydrochloride Experimental: 20 μg Drug: Sublingual film containing Sublingual Film containing dexmedetomidine hydrochloride 20 μg dexmedetomidine; Administration: Sublingual film single administration with containing dexmedetomidine repeat dose after 1 hour for the treatment of agitation associated with Schizophrenia Experimental: 60 μg Drug: Sublingual film containing Sublingual Film containing dexmedetomidine hydrochloride. 60 μg dexmedetomidine; Administration: Sublingual film single administration containing dexmedetomidine for the treatment of agitation associated with Schizophrenia Experimental: 80 μg Drug: Sublingual film containing Sublingual Film containing dexmedetomidine hydrochloride. 80 μg dexmedetomidine; Administration: Sublingual film single administration containing dexmedetomidine for the treatment of agitation associated with Schizophrenia Experimental: 120 μg Drug: Sublingual film containing 2 Sublingual Films, each dexmedetomidine hydrochloride. containing 60 μg Administration: Sublingual film dexmedetomidine; containing dexmedetomidine single administration of 2 for the treatment of agitation films associated with Schizophrenia Experimental: 180 μg Drug: Sublingual film containing 3 Sublingual Films, each dexmedetomidine hydrochloride. containing 60 μg Administration: Sublingual film dexmedetomidine; containing dexmedetomidine single administration of 3 for the treatment of agitation films associated with Schizophrenia

Number of Subjects (Planned and Analyzed):

An estimated 81 subjects in Stage 1 were planned in 3 cohorts (27 per cohort), however including the 2 additional cohorts (80 μg and 180 μg dexmedetomidine hydrochloride sublingual films), a total of 135 subjects were enrolled in 5 cohorts and analyzed.

Diagnosis and Main Criteria for Eligibility:

Inclusion Criteria:

-   -   1. Male and female patients between the ages of 18 to 65 years,         inclusive.     -   2. Patients who had met Diagnostic and Statistical Manual of         Mental Disorders, Fifth Edition (DSM-5) criteria for         schizophrenia, schizoaffective, or schizophreniform disorder.     -   3. Patients who were judged to be clinically agitated at         screening and baseline (pre-dose with a total score of ≥14 on         the 5 items (poor impulse control, tension, hostility,         uncooperativeness, and excitement) comprising the PANSS Excited         Component (PEC).     -   4. Patients who have a score of ≥4 on at least 1 of the 5 items         on the PEC at baseline (pre-dose).     -   5. Patients who read, understood and provide written informed         consent.     -   6. Patients who were in good general health prior to study         participation as determined by a detailed medical history,         physical examination, 12-lead ECG with rhythm strip, blood         chemistry profile, hematology, urinalysis and in the opinion of         the Principal Investigator.     -   7. Female participants, if of child-bearing potential and         sexually active, and male participants, if sexually active with         a partner of child-bearing potential, who agreed to use a         medically acceptable and effective birth control method         throughout the study and for one week following the end of the         study. Medically acceptable methods of contraception that could         be used by the participant and/or his/her partner include         abstinence, birth control pills or patches, diaphragm with         spermicide, intrauterine device (IUD), condom with foam or         spermicide, vaginal spermicidal suppository, surgical         sterilization and progestin implant or injection. Prohibited         methods include: the rhythm method, withdrawal, condoms alone,         or diaphragm alone.

Exclusion Criteria:

-   -   1. Patients with agitation caused by acute intoxication,         including positive identification of alcohol by breathalyzer or         drugs of abuse or non-prescription drugs (with the exception of         tetrahydrocannabinol (THC)) during urine screening.     -   2. Patients treated within 4 hours prior to study drug         administration with benzodiazepines, other hypnotics or oral or         short-acting intramuscular antipsychotics.     -   3. Treatment with alpha-1 noradrenergic blockers (terazosin,         doxazosin, tamsulosin, and alfuzosin, and prazocin) or other         prohibited medications.     -   4. Patients with significant risk of suicide or homicide per the         investigator's assessment, or any suicidal behaviour in last 6         months prior to screening.     -   5. Female patients who had a positive pregnancy test at         screening or were breastfeeding.     -   6. Patients who had hydrocephalus, seizure disorder, or history         of significant head trauma, stroke, transient ischemic attack,         subarachnoid bleeding, brain tumor, encephalopathy, meningitis,         Parkinson's disease or focal neurological findings.     -   7. History of syncope or other syncopal attacks, current         evidence of hypovolemia, orthostatic hypotension, a screening         heart rate of <55 beats per minutes (bpm) or systolic blood         pressure (SBP) <110 mmHg or diastolic blood pressure (DBP) <70         mmHg.     -   8. Patients with laboratory or ECG abnormalities considered         clinically significant by the investigator or qualified designee         [Advanced heart block (second-degree or above atrioventricular         block without pacemaker), diagnosis of Sick sinus syndrome] that         would have clinical implications for the patient's participation         in the study.     -   9. Patients with serious or unstable medical illnesses. These         include current hepatic (moderate severe hepatic impairment),         renal, gastroenterologic, respiratory, cardiovascular (including         ischemic heart disease, congestive heart failure),         endocrinologic, or hematologic disease.     -   10. Patients who had received an investigational drug within 30         days prior to the current agitation episode.     -   11. Patients who were unable to use the sublingual film or         considered by the investigator, for any reason, to be an         unsuitable candidate for receiving dexmedetomidine; e.g.,         patients with a history of allergic reactions to         dexmedetomidine.

Test Product, Dose and Mode of Administration:

Dexmedetomidine sublingual film (formulation of Examples 1 and 2 above) was tested in a small, solid-dose film formulations with dimensions of approximately 193.6 mm2 in area and 0.7 mm thick designed to completely dissolve in the SL space within 2-3 minutes. Reference therapy,

-   -   Dose and Mode of Administration:

Matching placebo films to be taken sublingually as described above.

Duration of Treatment: 1 day

Criteria for Evaluation: The primary endpoints in this study pertained to the efficacy, pharmacokinetics, safety, and tolerability of each dose level.

Efficacy: The efficacy of dexmedetomidine hydrochloride sublingual film on acute agitation was assessed using the Positive and Negative Syndrome Scale—Excited Component (PEC) scale. PEC comprised 5 items associated with agitation: poor impulse control, tension, hostility, uncooperativeness, and excitement; each scored 1 (minimum) to 7 (maximum). The PEC, the sum of these 5 subscales, thus ranging from 5 to 35.

Overall agitation and sedation were evaluated with the Agitation-Calmness Evaluation Scale (ACES), where 1 indicates marked agitation; 2—moderate agitation; 3—mild agitation; 4— normal behavior; 5—mild calmness; 6—moderate calmness; 7—marked calmness; 8—deep sleep; and 9—unarousable.

The change in agitation in response to treatment was also measured by the Clinical Global Impressions-Improvement (CGI-I). CGI-I scores range from 1 to 7: 0=not assessed (missing), 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse.

Pharmacokinetics:

Pharmacokinetic analysis was performed using dexmedetomidine plasma concentrations after administration of dexmedetomidine hydrochloride sublingual films. A dose proportionality analysis was conducted.

Safety and tolerability: AEs, clinical laboratory tests, ECG with rhythm strip, vital signs and signs of local irritation (buccal) were monitored for safety and tolerability.

Additional Assessments:

-   -   Demographic Data     -   Medical History     -   Prior and Concomitant Medication     -   Physical Examination and     -   Pregnancy testing

Statistical Analysis:

Efficacy Analyses: The primary efficacy endpoint of the study was the absolute change from baseline in PEC score at 120 mins (2 hours). The intent to treat population (ITT) was analyzed and consisted of all patients who took any study medication and who had both baseline and at least 1 efficacy assessment after dosing. Analyses were conducted using a restricted maximum likelihood repeated measures mixed model on change from baseline values with baseline as a covariate and timepoint, and its interaction with treatment groups as repeated measures using an unstructured covariance structure. Responder comparisons were made via Fisher's exact test.

Pharmacokinetic Analyses:

Pharmacokinetic analysis was conducted using a validated install of Phoenix® WinNonlin® version 8.1. Non-compartmental analysis was also conducted on the final audited data which consisted of a total of 135 participants in 5 cohorts receiving 20, 60, 80 (1×20 μg films and 1×60 μg films), 120 (2×60 μg films) and 180 μg (3×60 μg films) of dexmedetomidine sublingual films. All areas under the concentration-time curve (AUCs) were calculated using the linear trapezoidal method. Dose proportionality was assessed using a power model for PK parameters. Mean and individual concentration (sorted by dose level) versus time plots were generated.

Safety and Tolerability Analyses:

Safety data analysis was conducted on all subjects receiving at least 1 dose of study drug. The number and percentage of subjects experiencing 1 or more AEs were summarized by treatment, relationship to study drug, and severity. AEs were coded using Medical Dictionary for Regulatory Activities (Med DRA) terminology. Listings of subjects who experience withdrawal due to an AE, serious AEs and/or death were presented. Laboratory parameters were summarized by treatment using descriptive statistics and data listings of clinically significant abnormalities. Vital signs and ECG data were summarized by changes from baseline values at each dose level using descriptive statistics.

Sample Size Determination: The sample size is based on clinical experience and judgment relative to the study design and objectives in Stage 1. A sample size of at least 18 subjects on active drug in each dosing cohort should provide adequate clinical information to meet the objectives of the study.

All efficacy, safety, and tolerability measurements were conducted at regularly scheduled intervals as described in table 9.

TABLE 9 Schedule of Events Treatment Evaluation Day 1 Pre- Day 2 Dose¹ Follow- Day 7 −1 hr Up (+1) (+2) Screening to Post Dose Time¹ 24 hr End Activity Pre- time 10 20 30 45 1 1.5 2 4 6 8 (−9/ Day 3 of Time point treatment 0 min min min min hr hr hr hr hr hr +12 hr) Discharge Study Informed Consent X Medical History X Demographics X Weight X X Height X BMI X MINI X PANSS¹⁰ X X X Physical Exam X X Safety Labs⁵ X X X ECG with rhythm X X X X strip ⁹ Resting vital signs² X X X X X X X X X Orthostatic vital signs² X X X X X X Admit to Unit X Training/Review of X study drug administration Inclusion/Exclusion X X criteria Randomization X Study drug X administration⁸ PCRS¹¹ X X X X PEC³ X X X X X X X X X X X X ACES X X X CGI-Severity⁴ X X CGI-Improvement⁴ X X X X C-SSRS X X Buccal (SL) X X X X assessment for local irritation⁷ Visual Analog Scales X Likability Question X PK Sampling⁶ X X X  X* X X Concomitant X X X X X Medications Adverse Events X X X X X X X X X X X X X X X Abbreviations: ACES = Agitation-Calmness Scale; BMI = body mass index; CLIA = Clinical Laboratory Improvement Amendments; CGI-I = Clinical Global Impression-Improvement; CGI-S = Clinical Global Impression-Severity; C-SSRS = Columbia-Suicide Severity Rating Scale; DBP = diastolic blood pressure; ECG = electrocardiogram; MINI = Mini International Neuropsychiatric Interview; PANSS = Positive and Negative Syndrome Scale; PCRS = Placebo Control Reminder Script; PEC = Positive and Negative Syndrome Scale-Excited Component; PK = pharmacokinetic; SBP = systolic blood pressure; SL = sublingual; UDS = urine drug screen Notes to the Schedule of Events: ¹Pre-dose assessments had a window of 60 minutes prior to first dose. Timing of all susequent assessments was relative to the first dose. All post-dose assessments had a window of ±3 minutes until 2 hours and ±10 minutes until 8 hours. ²Resting vital signs (SBP, DBP and HR) will be taken at Screening, Pre-dose amd at 30 min, 1, 2, 4 and 8 hours post first dose. Triplicate measurements were performed in case of Systolic BP , 90 mmHg, Diastolic BP < 60 mmHg or Pulse < 60 bpm. Orthostatic measurements (SBP, DBP, HR, respiratory rate and temperature) were taken at Screening, Pre-dose, 2, 4 and 24 hours post first dose. Vital signs were done prior to each PK sample. ³PEC was performed at Screening, Pre-dose and at 10, 20, 30, 45 min; 1, 1.5, 2, 4, 6 and 24 hours post first dose. ⁴CGI-Severity was performed at Screening and pre-dose. CGI-Improvement was performed at 1, 2 and 4 hours post first dose. The PEC (preceded by the Placebo Control Reminder Script [PCRS], when required) was done prior to any other assessments. ⁵Safety Labs included chemistry, hematology, urinalysis, UDS (local lab)(only conducted at screening), alcohol breathalyzer (only conducted at screening), and urine pregnancy (only conducted at screening). Screening/enrollment labs: local labs drawn within 7 days prior to screening may suffice with the exception of urine drug screen. If results not available on the same day, a ‘desktop’ or non-CLIA test might be performed; to confirmed, results from a CLIA-certified laboratory should be recorded once available. ⁶PK blood samples were collected Predose (up to 15 min prior to first and, if applicable, second dose), 1, 1.5, 2, 4, 6, 8-10 hrs (collect one sample between 8 and 10 hours) and 24 hr after first dose. A sample may not be collected if the Physician indicates in source documents that the patient is in a mental state that was not conducive to PK sample collection. Non-compliance or refusal of all or any PK draw were exclusionary nor result in ET. All PK collections had a window of ±3 minutes with the exception of the 24 hour post-dose collection which had a window of ±1 hour. *For re-dosed subjects only: PK blood sample was collected at 2.5 hrs post first dose in addition to the other times. ⁷Buccal exam (at 30 min ±15, and other times ±30min) for local irritation performed by blinded staff. Day 2 follow up with ±1 day window. ⁸In the investigator's clinical judgement the same randomized dose might be repeated at 1 hr if there was no clinical effect (PEC change from baseline ≤ 40%) and in the absence of safety concerns. ⁹ ECG for pre-dose was not repeated if screening ECG was conducted on the day of dosing. ECGs collected following treatment were performed prior to PK assessments ¹⁰PANSS had administered at any time on the day of dosing prior to dosing and post-dose. Full PANSS was to be conducted in addition to stand alone PEC. ¹¹PCRS was performed immediately prior to the PEC

Results Summary:

1. Data Sets Analyzed

The number of subjects in each dataset were the same for all 3 populations (ie, Safety, ITT and PP) (Table 10). Additionally, the number of subjects in each dataset were the same for the pharmacokinetic population, as all subjects provided blood samples for analysis.

TABLE 10 Summary of Datasets Analyzed Dexmedetomidine sublingual film Placebo 20 μg 60 μg 80 μg 120 μg 180 μg Overall Dataset (N = 45) (N = 18) (N = 18) (N = 18) (N = 18) (N =18) (N = 135) Safety Population 45 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 135 (100.0) Intent-to-Treat Population 45 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 135 (100.0) Per-Protocol Population 45 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 135 (100.0)

Disposition:

A total of 135 subjects were enrolled and received study drug and comprised the Safety Population. Of the 135 subjects, all subjects completed the inpatient study drug treatment period; 127 subjects completed the end of the study period (i.e. study Day 7). Of the 8 subjects who did not complete the study, 7 subjects were lost to follow-up after discharge from the inpatient facility on study Day 3 and 1 subject withdrew from the study on study Day 3.

2. Demographics and Baseline Characteristics:

For subjects in the Safety Population (N=135), mean age was 47.6 years, the majority of subjects were male (65.9% [89/135]), and mean BMI was 30.58 kg/m2. Subjects were predominantly Black or African American (74.8% [101/135]) and not Hispanic or Latino (90.4% [122/135]). The majority of subjects in all treatment groups had a diagnosis of schizophrenia (assessed by the Mini-International Neuropsychiatric Interview [MINI-Plus] instrument). The proportion of subjects with schizophrenia ranged from 72.2% to 83.3% in the Dexmedetomidine sublingual film treatment groups. Based on MINI-Plus results, all subjects in the study met the inclusion criteria of having a diagnosis of schizophrenia, schizoaffective, or schizophreniform disorder (Table 11).

TABLE 11 Demographics and Baseline Characteristics Dexmedetomidine sublingual film Placebo 20 μg 60 μg 80 μg 120 μg 180 μg Overall Variable (N = 45) (N = 18) (N = 18) (N = 18) (N = 18) (N = 18) (N=135) Age (years) Mean (SD)  48.4  50.1  45.8  50.2  40.5  49.1  47.6 (10.88) (7.37) (10.87) (9.72) (8.40) (10.61) (10.26) Median  52.0  50.0  47.0  52.0  40.0  48.0  50.0 Min-Max  21,  29,  26,  26,  25,  26,  21, 63 59 63 63 54 64 64 Gender, n % Male  27  9  15  13  13  12  89 (60.0) (50.0) (83.3) (72.2) (72.2) (66.7) (65.9) Female  18  9  3  5  5  6  46 (40.0) (50.0) (16.7) (27.8) (27.8) (33.3) (34.1) Race, n % Black or African  37  13  11  12  15  13 101 American (82.2) (72.2) (61.1) (66.7) (83.3) (72.2) (74.8) White  7  5  7  6  2  4  31 (15.6) (27.8) (38.9) (33.3) (11.1) (22.2) (23.0) Asian  0  0  0  0  0  1  1 (5.6) (0.7) Multiple  1  0  0  0  0  0  1 (2.2) (0.7) Unknown  0  0  0  0  1  0  1 (5.6) (0.7) Ethnicity, n % Not Hispanic or  44  16  15  15  16  16 122 Latino (97.8) (88.9) (83.3) (83.3) (88.9) (88.9) (90.4) Hispanic or Latino  1  2  3  3  2  2  13 (2.2) (11.1) (16.7) (16.7) (11.1) (11.1) (9.6) Height (cm) Mean (SD) 171.15 169.29 174.08 174.90 175.33 174.87 172.85 (10.25) (10.63) (11.12) (10.66) (13.81) (8.95) (10.87) Median 169.00 170.30 174.05 175.90 175.70 175.25 173.00 Min-Max 149.9, 149.9, 150.5, 157.0, 137.0. 160.0, 137.0, 198.1 188.0 195.0 198.1 205.0 188.4 205.0 Weight (kg) Mean (SD)  86.86  86.92  94.89  92.84  90.54 100.53  91.05 (16.62) (18.83) (15.53) (19.77) (18.04) (19.10) (18.06) Median  84.10  82.50  97.10  91.95  90.80 100.45  91.00 Min-Max  56.8,  58.9,  64.9,  65.3,  57.2,  68.4,  56.8, 121.2 119.6 127.7 133.6 135.4 143.2 143.2 Body Mass Index (kg/m²) Mean (SD)  29.74  30.23  31.45  30.56  29.81  32.97  30.58 (5.61) (5.37) (5.47) (7.02) (6.96) (6.47) (6.06) Median  29.27  29.58  31.09  30.03  29.08  32.56  29.40 Min-Max  17.9,  20.9,  22.5,  20.9,  18.3,  24.8,  17.9, 41.5 40.3 42.8 44.5 45.4 45.4 45.4 Abbreviations: cm = centimeter; kg = kilogram; max = maximum; min = minimum; SD = standard deviation; Percentages are based on the number of Safety Population subjects in each treatment arm.

3. Efficacy

Dexmedetomidine sublingual film significantly improved the severity of agitation from baseline as measured by PEC, ACES scales and CGI-I scores. Key efficacy findings at 2 hours post-dose are presented below.

(a) Primary Efficacy Endpoint (PEC reduction): a reduction in the PEC score (PANSS or the Positive and Negative Syndrome Scale, Excitatory Component) for agitation was observed with rapid calming without excessive sedation at the clinical regulatory endpoint and at earlier time-points. The primary efficacy endpoint was the mean change from baseline in PEC total score at 2 hours (120 minutes) compared to placebo. There were 5 dose cohorts (20 μg, 60 μg, 80 μg, 120 μg and 180 μg) with 18 active patients (total of 90 patients) and 9 placebo patients (total of 45 patients) in each cohort. Active patients in each of the 5 dose cohorts were compared to placebo patients from all 5 cohorts (pooled placebo group). The change from baseline in PEC at 2 hours for patients treated with dexmedetomidine sublingual film was compared with placebo using a mixed model repeated measures (MMRM) analysis, with baseline PEC, treatment group, time, the interaction between treatment groups and time, and the interaction between baseline PEC and time as covariates.

The efficacy of dexmedetomidine hydrochloride sublingual film as measured by PEC reduction is dose-responsive and robust. The decrease from baseline in PEC score in the 180 μg dose group showed significant response with a −10.8 mean change from baseline (CFB) total PEC score at 2 hours post dosing compared to placebo (Table 12 and FIG. 1 ). Mean changes from baseline were −9.2 and −7.3 points, respectively for the 120 μg and 80 μg treatment groups, compared to placebo (−4.5 Mean change). LSM mean differences from placebo were −2.9 (P=0.0210), −4.6 (P=0.0003), and −6.3 (P<0.0001) for the 80 μg, 120 μg, and 180 μg treatment groups (table 11) Mean changes from baseline at 2 hours post dosing in the 20 μg and 60 μg groups were not significantly different than placebo. Additionally, as early onset of action is an important attribute for therapy in reducing agitation, the 180 μg group showed a statistically significant separation from placebo as early as 45 minutes post dosing (LS mean difference of −3.5 [P<0.0049]).

TABLE 12 Summary of Change from Baseline at all Timepoints in PANSS-PEC Total Score by Treatment Group (Intent to treat population) Dexmedetomidine Sublingual film Time Point Placebo 20 μg 60 μg 80 μg 120 μg 180 μg Statistics (N = 45) (N = 18) (N = 18) (N = 18) (N = 18) (N = 18) Baseline, n Mean (SD) 18.1 (2.37) 17.5 (2.33) 17.5 (2.07) 17.4 (1.42) 18.3 (1.64)   18.3 (2.95) 10 minutes post-dose Mean (SD) 16.0 (4.33) 16.2 (2.86) 15.1 (3.92) 15.2 (3.26) 17.8 (3.19)   16.8 (4.26) Change from baseline, mean (SD) −2.1 (3.60) −1.3 (1.67) −2.4 (3.45) −2.2 (3.01) −0.6 (2.31)  −1.5 (2.68) Change from baseline, LS mean (SE) −2.1 (0.5) −1.4 (0.7) −2.5 (0.7) −2.3 (0.7) −0.5 (0.7)  −1.4 (0.7) LSM difference (SE)^(a)   0.7 (0.9) −0.4 (0.9) −0.2 (0.9)   1.6 (0.9)    0.7 (0.9) 20 minutes post-dose Mean (SD) 15.2 (4.41) 15.1 (2.88) 14.1 (4.64) 14.2 (3.81) 15.8 (3.47)   15.6 (4.12) Change from baseline, mean (SD) −2.9 (3.60) −2.4 (2.33) −3.4 (4.29) −3.2 (3.89) −2.5 (3.03)  −2.7 (2.72) Change from baseline, LS mean (SE) −2.9 (0.5) −2.5 (0.8) −3.5 (0.8) −3.3 (0.8) −2.4 (0.8)  −2.6 (0.8) LSM difference (SE)^(a)   0.4 (1.0) −0.6 (1.0) −0.4 (1.0)   0.5 (1.0)    0.2 (1.0) 30 minutes post-dose Mean (SD) 14.8 (4.94) 14.2 (2.79) 13.1 (4.97) 12.7 (3.82) 15.0 (3.74)   14.2 (4.48) Change from baseline, mean (SD) −3.3 (4.46) −3.3 (3.07) −4.4 (4.67) −4.7 (3.82) −3.3 (3.56)  −4.1 (3.26) Change from baseline, LS mean (SE) −3.2 (0.6) −3.4 (0.9) −4.5 (0.9) −4.8 (0.9) −3.2 (0.9)  −4.0 (0.9) LSM difference (SE)^(a) −0.2 (1.1) −1.2 (1.1) −1.5 (1.1)   0.0 (1.1)  −0.7 (1.1) 45 minutes post-dose Mean (SD) 14.5 (4.88) 13.8 (3.15) 12.4 (5.41) 11.3 (4.80) 13.3 (4.66)   11.1 (5.08) Change from baseline, mean (SD) −3.6 (4.14) −3.7 (2.83) −5.1 (5.11) −6.1 (5.13) −5.1 (4.92)    7.2 (4.73) Change from baseline, LS mean (SE) −3.6 (0.7) −3.8 (1.0) −5.2 (1.0) −6.2 (1.0) −5.0 (1.0)  −7.1 (1.0) LSM difference (SE)^(a) −0.2 (1.2) −1.6 (1.2) −2.6 (1.2) −1.4 (1.2)  −3.5 (1.2) 1 hour post-dose Mean (SD) 14.0 (4.65) 13.0 (4.33) 11.4 (5.40) 10.9 (5.03) 10.9 (5.29)    9.2 (4.08) Change from baseline, mean (SD) −4.1 (4.29) −4.5 (3.67) −6.1 (5.49) −6.5 (5.28) −7.4 (5.48)  −9.1 (4.58) Change from baseline, LS mean (SE) −4.0, 0.7 −4.6 (1.1) −6.2 (1.1) −6.6 (1.1) −7.3 (1.1)  −9.0 (1.1) LSM difference (SE)^(a) −0.6 (1.3) −2.2 (1.3) −2.6 (1.3) −3.3 (1.3)  −5.0 (1.3) P-value^(b)   0.6647   0.0968   0.0488   0.0130    0.0002 1.5 hours post-dose Mean (SD) 13.8 (4.62) 12.1 (4.13) 11.3 (5.26) 10.8 (5.81) 10.8 (5.52)    7.8 (3.05) Change from baseline, mean (SD) −4.3 (4.43) −5.4 (3.96) −6.2 (5.24) −6.6 (6.05) −7.5 (5.57) −10.4 (4.38) Change from baseline, LS mean (SE) −4.3 (0.7) −5.5 (1.1) −6.3 (1.1) −6.7 (1.1) −7.4 (1.1) −10.4 (1.1) LSM difference (SE)ª −1.2 (1.3) −2.0 (1.3) −2.4 (1.3) −3.1 (1.3)  −6.1 (1.3) P-value^(b)   0.3661   0.1279   0.0743   0.0199  <0.0001 2 hours post-dose Mean (SD) 13.6 (4.56) 11.0 (3.87) 11.4 (5.07) 10.1 (5.45)   9.1 (4.20)    7.4 (2.68) Change from baseline, mean (SD) −4.5 (4.58) −6.5 (3.91) −6.1 (5.09) −7.3 (5.70) −9.2 (4.47) −10.8 (3.15) Change from baseline, LS mean (SE) −4.5 (0.7) −6.6 (1.0) −6.1 (1.0) −7.4 (1.0) −9.1 (1.0) −10.8 (1.0) LSM difference (SE)^(a) −2.1 (1.2) −1.7 (1.2) −2.9 (1.2) −4.6 (1.2)  −6.3 (1.2) P-value^(b)   0.0933   0.1850   0.0210   0.0003  <0.0001 4 hours post-dose Mean (SD) 13.7 (4.13)   9.4 (3.90) 11.2 (5.11) 10.2 (5.12)   9.1 (3.69)    7.3 (2.54) Change from baseline, mean (SD) −4.4 (4.44) −8.1 (4.32) −6.3 (5.22) −7.2 (5.48) −9.2 (4.02) −10.9 (3.61) Change from baseline, LS mean (SE) −4.3 (0.7) −8.1(1.0) −6.4 (1.0) −7.3 (1.0) −9.1 (1.0) −10.9 (1.0) LSM difference (SE)^(a) −3.8 (1.2) −2.1 (1.2) −2.9 (1.2) −4.8 (1.2)  −6.5 (1.2) P-value^(b)   0.0022   0.0895   0.0172   0.0001  <0.0001 6 hours post-dose Mean (SD) 13.1 (4.22) 10.0 (4.00) 11.9 (5.21) 10.1 (4.90)   9.3 (4.23)    7.2 (2.51) Change from baseline, mean (SD) −5.0 (4.79) −7.5 (4.03) −5.6 (5.19) −7.3 (5.30) −9.1 (5.00) −11.1 (3.47) Change from baseline, LS mean (SE) −4.9 (0.7) −7.6 (1.1) −5.6 (1.1) −7.4 (1.1) −9.0 (1.1) −11.0 (1.1) LSM difference (SE)^(a) −2.7 (1.3) −0.7 (1.3) −2.5 (1.3) −4.0 (1.3)  −6.0 (1.3) P-value^(b)   0.0375   0.5752   0.0490   0.0018  <0.0001 24 hours post-dose Mean (SD) 13.5 (3.91) 11.4 (3.58) 13.6 (4.10) 11.3 (4.18) 12.8 (3.59)    9.4 (4.82) Change from baseline, mean (SD) −4.6 (4.03) −6.1 (4.23) −3.9 (4.34) −6.1 (4.50) −5.6 (3.29)  −8.9 (3.53) Change from baseline, LS mean (SE) −4.6 (0.6) −6.2 (0.9) −4.0 (0.9) −6.2 (0.9) −5.5 (0.9)  −8.8 (0.9) LSM difference (SE)^(a) −1.6 (1.1)   0.6 (1.1) −1.6 (1.1) −0.9 (1.1)  −4.2 (1.1) P-value^(b)   0.1464   0.5697   0.1407   0.4310    0.0002 Note: subjects counts for all timepoints were 18 subjects for each dexmedetomidine sublingual film treatment group and 45 subjects for the placebo group ^(a)Treatment effect between dexmedetomidine sublingual film and placebo ^(b)p value comparing dexmedetomidine sublingual film and placebo

PEC Responder Analyses: The proportion of treatment responders, defined as those with a 40% decrease from baseline in PEC total score at 2 hours post dose, was greatest in the 180 group (94.4% [P<0.0001] for 180 μg, 68.8% [P=0.0158] for 120 μg, 58.8% for 80 μg [P=0.0759]) and significantly greater than placebo (31% responders) (Table 13 and FIG. 2 ). Response rates with 180 μg were significantly higher than placebo starting at 45 minutes post dose (44.4% versus 16.7%, respectively), continued to increase after 2 hours (to 94.4% at 4 and 6 hours) and sustained until at least 24 hours post-dose (83.3% versus 17.5%, respectively). Finally, the durability of calming effects of the 180 μg dose was remarkably prolonged with a sustained statistically significant reduction in PEC evident after 24 hrs. After a single dose in the 180 group, 83.3% of subjects maintained response after 24 hours with a mean PEC decrease of −8.9 (Mean CFB) compared to 37.5% in the 120 μg group (−5.6 Mean CFB) and 43.8% in the 80 group (−6.1 Mean CFB. Response rates over time for the 80 μg and 120 μg groups were high and similar between the 2 groups (Table 13 and FIG. 2 ).

TABLE 13 Percent of Responders in the PEC Score (Intent to treat Population) Dexmedetomidine Sublingual Film Time Point Placebo 20 μg 60 μg 80 μg 120 μg 180 μg Statistics (N = 45) (N = 18) (N = 18) (N = 18) (N = 18) (N = 18) 10 minutes post-dose Percent 11.9%   0% 12.5%  5.9%  6.3%  5.6% responders 20 minutes post-dose Percent 14.3%   0% 25.0% 23.5%  6.3%  5.6% responders 30 minutes post-dose Percent 21.4% 11.8% 37.5% 23.5% 12.5% 11.1% responders 45 minutes post-dose Percent 16.7% 17.6% 37.5% 41.2% 25.0% 44.4% responders 1 hour post-dose Percent 21.4% 29.4% 43.8% 58.8% 56.3% 55.6% responders P-value^(a) 0.5178 0.1091 0.0120 0.0236   0.0150 1.5 hours post-dose Percent 26.2% 41.2% 56.3% 52.9% 50.0% 77.8% responders P-value^(a) 0.3505 0.0612 0.0699 0.1190   0.0004 2 hours post-dose Percent 31.0% 58.8% 43.8% 58.8% 68.8% 94.4% responders P-value^(a) 0.0759 0.3735 0.0759 0.0158 <0.0001 4 hours post-dose Percent 21.4% 64.7% 50.0% 64.7% 68.8% 94.4% responders P-value^(a) 0.0024 0.0519 0.0024 0.0015 <0.0001 6 hours post-dose Percent 28.6% 64.7% 43.8% 58.8% 68.8% 94.4% responders P-value^(a) 0.0173 0.3510 0.0399 0.0075 <0.0001 24 hours post-dose Percent 17.5% 43.8% 26.7% 43.8% 37.5% 83.3% responders P-value^(a) 0.0838 0.4676 0.0838 0.1610 <0.0001 A responder is defined as a subject who achieved a ≥40% decrease from baseline in PEC score after dosing. The number of subjects with non-missing data in the dexmedetomidine sublingual film treatment groups were: 18 (180 μg), 17 (20 μg and 80 μg), and 16 (60 μg and 120 μg); 42 subjects in the placebo group had non-missing data. ^(a)P-value based on a comparison of dexmedetomidine sublingual film versus placebo via a Fisher's exact test

PANSS-EC (5 Items Subscale Scores): The PEC 5 subscale scores associated with agitation (ie, poor impulse control, tension, hostility, uncooperativeness, and excitement) were summarized in table 14, at 2 hours post dosing, significant improvements (ie, decreases) from baseline in all 5 PEC subscale scores were observed in the 80 μg, 120 μg and 180 μg groups compared to placebo; with the exception of “excitement” in the 80 μg group.

TABLE 14 Change from Baseline in PANSS-EC subscale scores at 2 hours post dosing in schizophrenia patients (Intent to treat Population) Dexmedetomidine Sublingual Film PANNS-EC Subscale Placebo 20 μg 60 μg 80 μg 120 μg 180 μg Statistics (N = 45) (N = 18) (N = 18) (N = 18) (N = 18) (N = 18) Poor Impulse Control Baseline, Mean (SD)   3.5 (0.63)   3.5 (0.62)   3.5 (0.62)   3.3 (0.49)   3.4 (0.50)   3.4 (0.70) 2 hours post-dose Mean (SD)   2.7 (0.87)   2.1 (1.13)   2.2 (1.11)   1.9 (1.06)   1.7 (0.75)   1.4 (0.70) Change from baseline, mean (SD) −0.8 (0.89) −1.4 (1.14) −1.3 (1.13) −1.4 (1.04) −1.7 (1.03) −2.0 (0.91) Change from baseline, LS mean (SE) −0.8 (0.1) −1.4 (0.2) −1.3 (0.2) −1.4 (0.2) −1.7 (0.2) −2.0 (0.2) LSM difference (SE)^(a) −0.6 (0.3) −0.5 (0.3) −0.6 (0.3) −0.9 (0.3) −1.2 (0.3) p value   0.0307   0.0810   0.0178   0.0009 <0.0001 Tension Baseline, Mean (SD)   4.0 (0.64)   3.8 (0.65)   3.6 (0.92)   3.8 (0.71)   4.1 (0.47)   4.1 (0.87) 2 hours post-dose Mean (SD)   3.0 (1.13)   2.4 (1.15)   2.3 (1.32)   2.1 (1.23)   1.9 (1.06)   1.5 (0.71) Change from baseline, mean (SD) −1.0 (1.24) −1.3 (1.14) −1.3 (1.19) −1.7 (1.45) −2.2 (0.92) −2.6 (1.04) Change from baseline, LS mean (SE) −0.9 (0.2) −0.5 (0.3) −0.5 (0.3) −0.8 (0.3) −1.2 (0.3) −1.6 (0.3) LSM difference (SE)a −0.5 (0.3) −0.5 (0.3) −0.8 (0.3) −1.2 (0.3) −1.6 (0.3) p value   0.1397   0.0947   0.0085   0.0002 <0.0001 Hostility Baseline, Mean (SD)   3.5 (0.73)   3.5 (0.62)   3.6 (0.70)   3.3 (0.77)   3.6 (0.62)   3.6 (0.61) 2 hours post-dose Mean (SD)   2.6 (1.12)   2.2 (0.71)   2.4 (1.04)   1.9 (1.11)   1.8 (0.79)   1.4 (0.51) Change from baseline, mean (SD) −0.9 (1.11) −1.3 (0.84) −1.2 (1.15) −1.4 (1.14) −1.7 (1.18) −2.2 (0.71) Change from baseline, LS mean (SE) −0.9 (0.1) −1.3 (0.2) −1.1 (0.2) −1.5 (0.2) −1.7 (0.2) −2.1 (0.2) LSM difference (SE)a −0.4 (0.3) −0.2 (0.3) −0.6 (0.3) −0.8 (0.3) −1.2 (0.3) p value   0.0973   0.3609   0.0272   0.0029 <0.0001 Uncooperativeness Baseline, Mean (SD)   3.3 (0.72)   3.2 (0.81)   3.3 (0.83)   3.4 (0.92)   3.4 (0.70)   3.2 (0.81) 2 hours post-dose Mean (SD)   2.5 (0.97)   2.0 (0.84)   2.2 (0.94)   2.0 (1.24)   1.7 (0.91)   1.4 (0.62) Change from baseline, mean (SD) −0.8 (0.98) −1.2 (1.06) −1.1 (1.11) −1.4 (1.33) −1.8 (1.06) −1.8 (0.81) Change from baseline, LS mean (SE) −0.8 (0.1) −1.3 (0.2) −1.1 (0.2) −1.4 (0.2) −1.7 (0.2) −1.8 (0.2) LSM difference (SE)a −0.5 (0.3) −0.3 (0.3) −0.6 (0.3) −1.0 (0.3) −1.0 (0.3) p value   0.0669   0.2607   0.0268   0.0004   0.0001 Excitement Baseline, Mean (SD)   3.8 (0.64)   3.5 (0.62)   3.6 (0.70)   3.5 (0.62)   3.8 (0.71)   3.9 (0.64) 2 hours post-dose Mean (SD)   2.7 (1.07)   2.3 (0.83)   2.3 (1.24)   2.1 (1.37)   1.9 (1.06)   1.6 (0.70) Change from baseline, mean (SD) −1.1 (1.11) −1.2 (0.88) −1.2 (1.22) −1.4 (1.46) −1.9 (1.02) −2.3 (0.77) Change from baseline, LS mean (SE) −1.1 (0.2) −1.3 (0.2) −1.3 (0.2) −1.5 (0.2) −1.8 (0.2) −2.2 (0.2) LSM difference (SE)a −0.2 (0.3) −0.2 (0.3) −0.4 (0.3) −0.8 (0.3) −1.2 (0.3) p value   0.3967   0.4394   0.1577   0.0081 <0.0001

Secondary Efficacy Endpoints:

Changes in secondary efficacy measures (i.e., ACES and CGI-I scores) at 2 hours post-dose were consistent with the results for PEC total scores and were indicative of improvement in symptoms of agitation after treatment with dexmedetomidine sublingual film.

ACES scores: A secondary objective for this study was to evaluate the duration of calming effect of dexmedetomidine sublingual thin film drug utilizing the Agitation-Calmness Evaluation Scale (ACES) collected at pre-dose, 2 hr, and 4 hr after first dose. The ACES assessment was consistent with the analysis of the primary endpoint, and met statistically significance for calming as measured by ACES at two hours compared to placebo in the three highest doses evaluated (80 μg; p=0.0150), (120 μg; p=0.0003) and (180 μg; p<0.0001). At 2 hours after dosing, subjects in the 80 μg, 120 μg, and 180 μg treatment groups showed significantly greater improvements relative to placebo in ACES scores (+2.3 [P=0.0150], +3.1 [P=0.0003], and +4.2 [P=<0.0001], respectively, compared to placebo of +1.2). The improvements at 4 hours post-dose were similar (+2.1 [P=0.0252], +3.2 [P=<0.0001], and +4.1 [P=<0.0001], placebo was +1.1). (Table 15 and FIG. 3 ). In terms of calming effect (as measured by ACES scores), mean scores in 120 μg and 180 μg groups increased from a baseline of approximately 2 “moderate agitation” to 5.1 “mild calmness” and 6.2 “moderate calmness,” respectively at 2 hours post-dose, compared with a score of 3.4 “mild agitation” in the placebo group. The improvements in calmness in the groups were statistically significant with P values of 0.0003 and <0.0001, respectively, compared with placebo (Table 15).

Time to resolution of agitation: The percentage of subjects achieving an ACES score of at least 4 (normal)) at 2 and 4 hours post dosing is displayed in FIG. 3 . At 2 and 4 hours after dosing, the percentage of subjects who achieved a ACES score of at least 4, which indicated resolution of agitation, was significantly greater in the 120 μg group (72.2% [P=0.0045] and 77.8% [P=0.0016], respectively) and the 180 μg group (88.9% [P<0.0001] and 83.3% [P=0.0002], respectively) compared with the placebo group (31.1% at both 2 and 4 hours post-dose). In terms of sedation (as measured by ACES scores) the results indicated that a total of 9 subjects in the treatment groups had scores of 8 “deep sleep” at 2 hours and/or 4 hours post-dose, however, no subject in any of the treatment groups had a score of 9 “unarousable.” (Table 16). Calming effect was durable lasting at least 6 hours as evidenced by separation from placebo for 80 μg, 120 μg and 180 μg dose groups.

TABLE 15 Change from Baseline in ACES Score at 2 and 4 hours post dosing (Intent to treat population) Dexmedetomidine Sublingual Film Placebo 20 μg 60 μg 80 μg 120 μg 180 μg Time Post dose (N = 45) (N = 18) (N = 18) (N = 18) (N = 18) (N = 18) Baseline, n Mean (SD) 2.1 (0.55) 2.3 (0.49) 2.2 (0.55) 2.2 (0.55)   2.0 (0.34)   1.9 (0.54) 2 hours post-dose Mean (SD) 3.4 (1.55) 3.8 (1.11) 4.2 (1.70) 4.6 (2.25)   5.1 (2.05)   6.2 (1.58) Change from baseline, mean (SD)^(a) 1.2 (1.46) 1.4 (1.29) 2.0 (1.71) 2.3 (2.43)   3.1 (2.03)   4.2 (1.83) Change from baseline, LS mean (SE)^(b) 1.2 (0.3) 1.6 (0.4) 2.1 (0.4) 2.4 (0.4)   3.0 (0.4)   4.1 (0.4) LSM difference (SE)^(c) 0.4 (0.5) 0.8 (0.5) 1.2 (0.5)   1.8 (0.5)   2.9 (0.5) P-value^(d) 0.4371 0.0795 0.0150   0.0003 <0.0001 4 hours post-dose Mean (SD) 3.2 (1.42) 4.4 (1.54) 3.9 (1.76) 4.3 (2.22)   5.2 (1.72)   6.0 (1.75) Change from baseline, mean (SD)^(a) 1.1 (1.40) 2.1 (1.53) 1.7 (1.81) 2.1 (2.19)   3.2 (1.69)   4.1 (2.04) Change from baseline, LS mean (SE)^(b) 1.1 (0.3) 2.3 (0.4) 1.8 (0.4) 2.2 (0.4)   3.1 (0.4)   3.9 (0.4) LSM difference (SE)^(c) 1.2 (0.5) 0.7 (0.5) 1.1 (0.5)   2.0 (0.5)   2.8 (0.5) P-value^(d) 0.0164 0.1524 0.0252 <0.0001 <0.0001 ^(a)Change from baseline (pre-dose) ACES score, with positive values in favor of improvement. ^(b)Least square mean and standard error per treatment group. ^(c)Treatment Effect: Least square mean difference, standard error, and 95% confidence intervals between Dexmedetomidine sublingual film and Placebo. ^(d)p value comparing Dexmedetomidine sublingual film and Placebo

TABLE 16 Subjects Rates with an ACES Scores of 8 (Deep Sleep) or 9 (Unarousable Sleep) for all dose groups Number of Number of Number of Dose Subjects Subjects Subjects ACES Score Group at Baseline at 2 hr at 4 hr Deep Sleep Placebo 0 0 0 ACES Score = 8  20 μg 0 0 1  60 μg 0 0 0  80 μg 0 1 1 120 μg 0 2 0 180 μg 0 2 3 Unarousable Sleep Placebo 0 0 0 ACES Score = 9  20 μg 0 0 0  60 μg 0 0 0  80 μg 0 0 0 120 μg 0 0 0 180 μg 0 0 0

CGI-I scores: Mean baseline CGI-S scores were comparable across all treatment groups (range: 3.9 to 4.3). The CGI-S scores indicated that the subjects were clinically agitated (ie, moderately ill) prior to dosing (Table 17). Significant improvements in agitation (ie, lower CGI-I scores) from baseline were observed at 1 hour after dosing in the dexmedetomidine sublingual film 120 μg and 180 μg groups. Mean (SD) scores were 2.3 (1.13) and 2.1 (0.87), respectively, compared with 3.0 (0.98) in the placebo group (Table 18). LSM differences from placebo were −0.7 (P=0.0167) and −0.9 (P=0.0019) in the 120 μg and 180 μg groups, respectively. Significant improvements in agitation (i.e. lower mean CGI-I scores) from baseline were observed at 2 hours post-dose in the 120 μg group (1.9 [P=0.0007]) and in the 180 μg group (1.4 [P<0.0001]), compared with a mean score of 3 in the placebo group (Table 18). LSM differences from placebo were −1.1 (P=0.0007) and −1.6 (P<0.0001). Significant improvements were also observed at 4 hours post-dose in the dexmedetomidine sublingual film 120 μg and 180 μg groups The percentage of subjects achieving CGI-I scores of 1 or 2 (‘very much improved’ or ‘much improved’) at 2 hours post-dose was significantly higher in the 120 μg group (66.7% [P=0.0125]) and in the 180 dose group (94.4% [P<0.0001]), compared with placebo (31.0%). Significant improvements were also observed at 1 hour and at 4 hours after dosing for both treatment groups (Table 19 and FIG. 4 ).

TABLE 17 CGI-S Mean Scores at Baseline (Intent to treat Population) Dexmedetomidine Sublingual Film Time Point Placebo 20 μg 60 μg 80 μg 120 μg 180 μg Statistics (N = 45) (N = 18) (N = 18) (N = 18) (N = 18) (N = 18) Number of subjects 45 18 18 18 18 18 Baseline (pre-dose) Mean (SD) 4.2 (0.44) 3.9 (0.47) 4.1 (0.68) 4.1 (0.32) 4.3 (0.57) 4.3 (0.46) Minimum-Maximum 3.0-5.0 3.0-5.0 3.0-5.0 4.0-5.0 3.0-5.0 4.0-5.0

TABLE 18 Summary of Change from Baseline for CGI-I Score (Intent to treat Population) Dexmedetomidine Sublingual Film Time Point Placebo 20 μg 60 μg 80 μg 120 μg 180 μg Statistics (N = 45) (N = 18) (N = 18) (N = 18) (N = 18) (N = 18) Number of subjects 45 18 18 18 18 18 30 minutes post-dose Mean (SD) 3.1 (1.04)  3.1 (0.76)  2.8 (1.15)  3.2 (1.15)  3.1 (0.76)  3.1 (0.76) LS mean (SE) ^(a) 3.2 (0.1)  3.1 (0.2) 2.8 (0.2) 3.2 (0.2) 3.1 (0.2) 3.1 (0.2) LSM difference (SE)^(b) −0.1 (0.3)  −0.4 (0.3)  −0.0 (0.3)  −0.1 (0.3)  −0.1 (0.3)  P-value^(c) 0.7431 0.1778 0.9022 0.7431 0.7431 1 hour post-dose Mean (SD) 3.0 (0.98)  2.9 (0.83)  2.4 (1.20)  2.8 (1.42)  2.3 (1.13)  2.1 (0.87) LS mean (SE)^(a) 3.0 (0.2)  2.9 (0.3) 2.4 (0.3) 2.8 (0.3) 2.3 (0.3) 2.1 (0.3) LSM difference (SE)^(b) −0.1 (0.3)  −0.6 (0.3)  −0.2 (0.3)  −0.7 (0.3)  −0.9 (0.3)  P-value^(c) 0.7098 0.0645 0.5769 0.0167 0.0019 2 hours post-dose Mean (SD) 3.0 (1.09)  2.4 (0.98)  2.3 (1.13)  2.6 (1.54)  1.9 (1.00)  1.4 (0.61) LS mean (SE) ^(a) 3.0 (0.2)  2.4 (0.3) 2.3 (0.3) 2.6 (0.3) 1.9 (0.3) 1.4 (0.3) LSM difference (SE)^(b) −0.6 (0.3)  −0.7 (0.3)  −0.4 (0.3)  −1.1 (0.3)  −1.6 (0.3)  P-value^(c) 0.0701 0.0190 0.2034 0.0007 <0.0001 4 hours post-dose Mean (SD) 3.0 (1.08)  2.4 (0.92)  2.8 (1.22)  2.6 (1.60)  1.8 (0.73)  1.4 (0.62) LS mean (SE) ^(a) 3.0 (0.2)  2.4 (0.3) 2.8 (0.3) 2.7 (0.3) 1.8 (0.3) 1.4 (0.3) LSM difference (SE)^(b) −0.6 (0.3)  −0.2 (0.3)  −0.3 (0.3)  −1.2 (0.3)  −1.5 (0.3)  P-value^(c) 0.0516 0.5071 0.4139 0.0001 <0.0001 Clinical Global Impression-Improvement scores range from 1 (Very much improved) to 7 (Very much worse). Test statistics and estimates are from a restricted maximum likelihood repeated measures mixed model on observed values with timepoint and its interaction with treatment group as repeated measures using an unstructured covariance structure. ^(a) Least square mean and standard error per treatment group. The corresponding estimates for the placebo group are not included as they vary with the dexmedetomidine sublingual film dosing group being compared. ^(b)Treatment Effect: Least square mean difference, standard error, and 95% confidence intervals between dexmedetomidine sublingual film and Placebo ^(c)P value comparing dexmedetomidine sublingual film and Placebo

TABLE 19 Percent of Responders in the CGI-I Scale over Time (Intent-to-Treat Population) Dexmedetomidine sublingual film Time Point Placebo 20 μg 60 μg 80 μg 120 μg 180 μg Statistics (N = 45) (N = 18) (N = 18) (N = 18) (N = 18) (N = 18) 30 minutes post-dose Percent 22.2% 22.2% 38.9% 27.8% 22.2% 22.2% responders P-value^(a) 1.000 0.2158 0.7457 1.000   1.000 1 hour post-dose Percent 24.4% 38.9% 44.4% 44.4% 55.6% 72.2% responders P-value^(a) 0.3549 0.1383 0.1383 0.0361   0.0011 2 hours post-dose Percent 31.1% 55.6% 55.6% 50.0% 66.7% 94.4% responders P-value^(a) 0.0896 0.0896 0.2462 0.0125 <0.0001 4 hours post-dose Percent 32.6% 55.6% 44.4% 57.1% 83.3% 94.4% responders P-value^(a) 0.1499 0.3968 0.1231 0.0005 <0.0001 ^(a)P-value based on a comparison of dexmedetomidine sublingual film versus placebo via a Fisher's exact test

Pharmacokinetic Results:

Pharmacokinetic analysis was conducted using a validated install of Phoenix® WinNonlin® version 8.1. Non-compartmental analysis was also conducted on the final audited data which consisted of a total of 135 participants in 5 cohorts receiving 20, 60, 80 (1×20 μg films and 1×60 μg films), 120 (2×60 μg films) and 180 μg (3×60 μg films) of dexmedetomidine sublingual film. Measurable concentrations of dexmedetomidine were observed at the first collected post dose plasma sample (1 hr) for all dose levels and tabulated in table 20. There were no measurable concentrations at pre-dose (0 hr) at any dose level. Measurable concentrations of dexmedetomidine were observable until 8 hr for all dose levels with measurable concentrations at 24 hr in some subjects at each dose level (Table 20; FIGS. 5A and 5B). Dexmedetomidine sublingual film is absorbed rapidly with maximum concentration achieved on average within about 2.5 hours after administration. The median Tmax ranged from 1.50-2.31 hr while the median t1/2 ranged from 2.36-3.06 hr across the 5 dose levels. The exposure (Cmax and AUC) increased in an approximately dose proportional manner within the dose range (20 μg-180 μg) studied after single administration. The median Cmax ranged from about 40 ng/L to about 500 ng/L. After absorption, it was eliminated with about a 3-hour half-life which was consistent across dose groups. In 20 μg dose group, 8 of 18 subjects were given a second dose of dexmedetomidine sublingual film, the exposure (Cmax and AUC) was about 2-fold higher than in the group which was not redosed

Observed exposures following a single dose of 180 μg (Mean Cmax: 379 ng/L; Mean AUC 2881 ng/L) (Table 20) are significantly below the mean exposures (IV PRECEDEX® at approved dose is estimated): Cmax: 1339 ng/L; AUC: 31713 ng·h/L (PKPD18-1054) with the highest approved dose of dexmedetomidine.

TABLE 20 Individual and summary statistics of PK parameter estimates of dexmedetomidine in plasma after administration of dexmedetomidine sublingual film in schizophrenia patients. Dose Re- Cmax Tmax AUClast AUCinf_obs t1/2 Cohort (ug) dose Subject ID (ng/L) (hr) (hr*ng/L) (hr*ng/L) (hr) 1 20 No 01-001 35.54 1.50 224.01 NC NC 01-002 38.55 1.50 186.08 NC 3.79 01-010 59.82 1.00 104.40 NC 2.12 01-026 14.07 4.02 57.43 NC NC 07-015 33.41 1.53 177.60 NC 5.36 07-030 34.31 2.00 176.11 203.81 2.29 10-027 35.38 2.00 184.37 NC 3.64 23-016 69.05 1.48 264.45 NC 2.95 23-018 40.37 1.97 154.62 186.40 3.17 23-020 38.49 1.95 190.81 226.26 2.51 N 10 10 10 3 8 Mean 39.90 1.89 171.99 205.49 3.23 SD 15.02 0.81 57.74 19.98 1.05 CV % 37.64 42.89 33.57 9.72 32.61 Min 14.07 1.00 57.43 186.40 2.12 Median 37.02 1.74 180.99 203.81 3.06 Max 69.05 4.02 264.45 226.26 5.36 Geometric 37.16 1.78 160.36 204.85 3.0 9 Mean Geometric 43.89 36.99 45.49 9.72 31.23 CV % 1 20 Yes 01-009 130.44 2.00 662.46 NC 3.94 01-013 122.23 2.00 486.82 563.33 2.73 05-007 49.87 2.50 230.06 NC 4.02 05-008 66.64 2.12 272.47 304.52 2.00 05-021 86.86 2.50 410.74 NC 3.10 05-023 52.29 2.50 236.04 NC NC 05-024* 138.69 8.03 1912.52 NC NC 07-028 125.70 2.00 476.62 519.25 1.81 N 8 8 8 3 6 Mean 96.59 2.96 585.96 462.37 2.93 SD 36.95 2.06 556.20 138.47 0,94 CV % 38.26 69.85 94.92 29.95 31.98 Min 49.87 2.00 230.06 304.52 1.81 Median 104.54 2.31 443.68 519.25 2.91 Max 138.69 8.03 1912.52 563.33 4.02 Geometric 89.71 2.61 453.42 446.60 2.80 Mean Geometric 44.50 49.35 78.77 34.37 34.49 CV % 2 60 No 01-044 93.67 1.00 442.23 NC 3.10 01-047 73.42 1.00 265.85 293.67 2.23 01-055 113.35 1.50 474.46 562.60 2.87 01-056 154.79 1.50 413.53 428.64 1.48 03-036 83.52 1.55 347.11 369.07 1.62 05-050 121.52 1.00 355.87 381.27 1.84 05-052 105.84 1.50 330.30 369.14 2.36 06-033 253.14 1.45 737.87 834.44 2.37 06-034 206.42 1.53 887.27 1007.71 2.35 06-041 144.27 2.07 1714.29 1882.10 6.98 06-043 186.40 1.02 748.96 877.63 2.53 07-048 201.12 0.98 874.85 1030.25 2.81 08-046* 93.22 2.00 346.61 NC NC 09-042 146.17 3.95 2072.02 2195.38 5.43 10-032 136.25 1.50 650.22 NC NC 10-035 127.27 1.50 519.54 616.68 2.78 10-039 144.93 1.00 603.55 691.00 2.27 10-045 127.30 1.50 495.69 548.50 2.30 N 18 18 18 15 16 Mean 139.59 1.53 680.71 805.85 2.83 SD 47.22 0.69 481.66 555.95 1.42 CV % 33.83 45.0 70.76 68.89 50.15 Min 73.42 0.98 265.85 293.67 1.48 Median 131.78 1.50 507.61 616.68 2.36 Max 253.14 3.95 2072.02 2195.38 6.98 Geometric 132.56 1.43 575.95 674.14 2.60 Mean Geometric 33.88 36.02 59.93 65.01 40.94 CV % 3 120 No 01-059 128.89 2.00 1143.72 1192.51 5.28 01-062 380.78 2.00 2927.15 2958.80 3.64 01-065 393.58 4.00 3935.47 4063.95 4.62 01-080 316.57 1.00 1536.77 1538.84 2.60 01-082 315.51 4.00 4156.65 4371.55 5.32 01-086 201.58 1.00 915.85 918.48 2.56 03-068 308.19 1.02 1039.39 1039.79 2.02 06-077 108.84 3.82 585.94 586.93 2.59 06-078 228.53 1.47 NC NC NC 06-083 154.65 1.47 592.96 593.28 2.01 06-084 160.33 1.47 682.91 683.47 2.59 07-066 366.09 2.00 3920.86 4012.15 4.35 10-063 184.22 2.00 NC NC 3.50 10-076 149.11 2.00 990.19 989.76 2.81 23-069 286.88 2.00 1230.19 1230.90 1.98 23-070 243.63 1.52 NC NC 3.21 23-073* 125.62 4.00 NC NC NC 23-074 233.12 1.55 1162.59 1166.09 2.83 N 18 18 18 14 16 Mean 238.12 2.13 1513.91 1810.47 3.25 SD 92.98 1.06 1264.13 1395.65 1.1 CV % 39.05 50.03 83.50 77.09 34.27 Min 108.84 1.00 499.50 586.93 1.98 Median 230.83 2.00 970.38 1179.30 2.82 Max 393.58 4.00 4158.05 4371.55 5.32 Geometric 220.53 1.91 1169.33 1411.79 3.08 Mean Geometric 42.89 49.10 78.73 81.15 33.71 CV % 4 180 No 01-089 490.60 1.00 5498.99 5592.92 3.92 01-097 636.45 1.50 2508.31 2676.44 1.76 01-105 685.45 1.00 2628.09 3126.77 2.73 01-111* 88.10 8.00 1311.33 NC NC 05-088 127.77 1.02 520.53 569.19 2.03 05-098 563.94 1.47 2435.38 2644.08 1.86 05-100 487.88 1.47 4630.43 4705.04 3.90 06-091 592.99 3.98 6835.79 7310.47 5.92 06-093 406.57 2.07 2173.00 NC 3.22 07-095* 443.70 2.00 1911.81 NC NC 10-090 546.65 2.00 3808.10 NC 5.19 10-123 797.37 1.50 8928.20 9468.70 5.80 10-127 640.01 2.00 2444.45 2746.20 2.30 10-129 483.07 2.00 3578.09 4340.66 9.65 23-103 225.12 1.98 1034.07 1140.28 1.90 23-104 227.51 1.97 1086.53 NC 2.94 23-125 237.95 1.98 943.23 1049.33 2.10 23-126 224.88 1.98 1243.11 NC 2.84 N 18 18 18 12 16 Mean 439.22 2.16 2973.31 3780.85 3.63 SD 206.41 1.60 2255.10 2663.22 2.12 CV % 46.99 73.99 75.84 70.44 58.29 Min 88.10 1.00 520.53 569.19 1.76 Median 485.48 1.98 2439.91 2936.49 2.89 Max 797.37 8.00 8928.20 9468.70 9.65 Geometric 379.13 1.87 2294.38 2881.18 3.20 Mean Geometric 68.19 52.19 87.67 100.34 53.08 CV % 5 80 No 01-144 160.18 2.00 784.24 917.99 2.49 02-133 142.99 2.03 747.42 886.35 2.41 02-142 222.79 2.00 2480.66 2594.62 5.37 03-112 68.41 1.55 416.50 NC NC 03-114 70.46 1.03 244.38 NC NC 03-120 107.00 1.53 450.79 531.82 2.67 03-134 135.30 1.55 759.89 894.79 2.57 08-092 167.57 1.88 938.26 NC NC 08-094 199.63 1.45 684.60 737.33 1.88 08-109 102.29 1.50 561.56 NC 3.12 09-137 151.89 2.25 635.19 767.51 3.07 20-115 224.70 1.22 1114.91 1366.03 2.72 20-138 175.94 4.32 2218.17 2334.99 5.33 20-140 182.32 1.58 659.20 702.28 1.78 20-141 253.29 1.20 888.38 NC 4.75 22-131 184.62 2.12 1020.28 NC 2.96 24-116 315.11 1.53 1145.23 1305.66 2.53 24-130 139.94 4.03 1325.85 1375.38 4.93 N 18 18 18 12 15 Mean 166.91 1.93 948.64 1201.23 3.24 SD 62.75 0.88 579.45 651.50 1.22 CV % 37.59 45.71 61.08 54.24 37.76 Min 68.41 1.03 244.38 531.82 1.78 Median 163.88 1.57 772.07 906.39 2.72 Max 315.11 4.32 2480.66 2594.62 5.37 Geometric 155.27 1.79 816.58 1071.37 3.05 Mean Geometric 42.27 38.50 60.56 51.21 36.76 CV %

3. Safety and Tolerability:

Dexmedetomidine sublingual film (formulations of Example 1 and 2) was well tolerated and had a favourable safety profile in the treatment of subjects with agitation. An overview of subjects who experienced at least 1 treatment emergent adverse event (TEAE) by treatment group for the safety population is given in Tables 21 and 22. Overall, a total of 55 subjects (40.7% [55/135]) experienced a least 1 TEAE. The proportion of subjects who experienced TEAEs was similar in the 80 μg, 120 μg, and 180 μg dose groups (55.6%, 66.7%, and 66.7%, respectively). In comparison, the proportion of subjects with TEAEs was lower in the 20 μg and 60 μg dose groups (27.8% and 33.3%, respectively) and the placebo group (22.2%). Most (81.1%) of the TEAEs in all treatment groups were mild in severity. Almost all (90.9%) of the TEAEs were considered to be related to study drug in all treatment groups. None of the subjects experienced a TEAE that was considered to be severe in intensity. There were no deaths, SAEs, or discontinuations due to an AE reported in this study (Tables 21 and 22).

The TEAEs reported in this study were consistent with known common side effects of dexmedetomidine, namely, dry mouth, bradycardia, hypotension, and somnolence (Table 21).

The most frequently reported TEAE was somnolence with 26 subjects experiencing the event of which 20 events were mild in severity and 4 events were moderate in severity. Incidences for somnolence in the groups were 16.7% (20 μg and 60 μg), 22.2% (120 μg), 33.3% (80 μg), and 44.4% (180 μg); incidence in the placebo group was 4.4%. The second most frequently reported TEAE was dry mouth which was reported by 5.6%, 16.7%, 16.7%, and 11.1% of subjects in the 20 μg, 80 μg, 120 μg, and 180 μg groups, respectively, compared with 13.3% of subjects in the placebo group. No subject in the 60 μg dose group reported an event of dry mouth. All cases of dry mouth were mild in severity.

In the dexmedetomidine hydrochloride treatment groups, TEAEs associated with vital signs were: hypotension in 6 subjects (n=2 [120 μg], n=4 [180 μg]), orthostatic hypotension (n=1 [80 μg], n=1 [120 μg], and n=1 [180 μg), and bradycardia (n=1 [20 μg]). All subjects recovered from the events.

Three laboratory related adverse events (3×upper limit of normal for T Bili, 3+ Glucose in urine, and 4+ Protein in urine) were being followed-up at each respective clinical site and remained unresolved at this time. Otherwise there were no clinically significant changes in laboratory parameters and ECG assessments. No physical examination finding was considered clinically significant by the investigators. None of the subjects had a negative reaction (i.e. local irritation) to study drug as determined by buccal examination.

Also, the dose dependent decreases in SBP and DBP were observed with maximum changes at 2 hours post-dose:

-   -   SBP: −4.6 (9.63), −5.6 (10.85), −8.2 (11.50), −12.1 (20.50), and         −14.7 (12.09) mmHg in the 20 μg, 60 μg, 80 μg, 120 μg, and 180         μg groups, respectively, and +1.2 (9.23) mmHg in the placebo         group.     -   DBP: 0.3 (10.39), −5.3 (7.86), −6.4. (8.05), −7.8 (9.40), and         −6.6 (6.41) mmHg in the 20 μg, 60 μg, 80 μg, 120 μg, and 180 μg         groups, respectively, and +0.2 (7.82) mmHg in the placebo group.     -   HR: −0.1 (6.24), −3.9 (9.13), −0.8 (8.39), −2.2 (13.03), and         −10.7 (12.97) bpm in the 20 μg, 60 μg, 80 μg, 120 μg, and 180 μg         groups, respectively, and −0.8 (8.29) bpm in the placebo group.

Further, the orthostatic measurements of SBP, DBP, and HR were performed after the subject had been standing for a total of 5 minutes.

Mean changes from baseline at hours 2 postdosing for standing SBP, DBP, and HR are provided below (FIGS. 7A, 7B and 7C). These changes are similar to the changes from baseline values for resting measurements for SBP, DP, and HR (FIGS. 6A, 6B and 6C). Total of 3 subjects (1 in each dose groups 80 μg, 120 μg, and 180 μg) experienced TEAEs of orthostatic hypotension.

Mean (±SD) changes from baseline at 2 hours postdosing for standing SBP, DBP, and HR were:

-   -   SBP: −3.1 (8.34), −4.6 (9.04), −12.6 (12.83), −11.9 (16.43) and         −15.0 (11.3) mmHg in the 20 μg, 60 μg, 80 μg, 120 μg, and 180 μg         dose groups, respectively, and +0.5 (8.35) mmHg in the placebo         group.     -   DBP: −1.4 (6.97), −4.2 (4.78), −6.7 (8.49), −6.9 (7.86), and         −7.1 (8.51) mmHg in the 20 μg, 60 μg, 80 μg, 120 μg, and 180 μg         dose groups, respectively, and −1.3 (7.36) mmHg in the placebo         group.     -   HR: 0.6 (7.92), −4.3 (11.87), −1.1 (10.47), −1.7 (13.98), and         −10.4 (10.08) bpm in the 20 μg, 60 μg, 80 μg, 120 μg, and 180 μg         dose groups, respectively, and −0.3 (9.88) bpm in the placebo         group.

TABLE 21 Treatment Emergent Adverse Events by System Organ Class and Preferred Term During the Treatment Period(Safety Population) Dexmedetomidine sublingual film System Organ Class Placebo 20 μg 60 μg 80 μg 120 μg 180 μg Preferred Term (N = 45) (N = 18) (N = 18) (N = 18) (N = 18) (N = 18) Any AEs 10 (22.2) 5 (27.8) 6 (33.3) 10 (55.6) 12 (66.7) 12 (66.7) Nervous system disorders 6 (13.3) 4 (22.2) 4 (22.2) 8 (44.4) 9 (50.0) 9 (50.0) Somnolence 2 (4.4) 3 (16.7) 3 (16.7) 6 (33.3) 4 (22.2) 8 (44.4) Headache 2 (4.4) 1 (5.6) 0 1 (5.6) 3 (16.7) 0 Dizziness 2 (4.4) 0 2 (11.1) 1 (5.6) 1 (5.6) 0 Paraesthesia 0 0 0 1 (5.6) 1 (5.6) 0 Hypoaesthesia 0 0 1 (5.6) 0 0 0 Sedation 0 0 0 0 0 1 (5.6) Gastrointestinal disorders 7 (15.6) 2 (11.1) 1 (5.6) 4 (22.2) 4 (22.2) 2 (11.1) Dry mouth 6 (13.3) 1 (5.6) 0 3 (16.7) 3 (16.7) 2 (11.1) Constipation 0 0 1 (5.6) 1 (5.6) 0 0 Diarrhoea 0 0 0 0 1 (5.6) 0 Dyspepsia 0 1 (5.6) 0 0 0 0 Nausea 1 (2.2) 0 0 0 0 0 Toothache 1 (2.2) 0 0 0 0 0 Vascular disorders 0 0 0 1 (5.6) 3 (16.7) 5 (27.8) Hypotension 0 0 0 0 2 (11.1) 4 (22.2) Orthostatic hypotension 0 0 0 1 (5.6) 1 (5.6) 1 (5.6) Investigations 3 (6.7) 0 1 (5.6) 0 1 (5.6) 1 (5.6) Alanine aminotransferase increased 1 (2.2) 0 0 0 0 0 Aspartate aminotransferase increased 1 (2.2) 0 0 0 0 0 Blood bilirubin increased 0 0 1 (5.6) 0 0 0 Glucose urine present 0 0 0 0 1 (5.6) 0 Heart rate increased 1 (2.2) 0 0 0 0 0 Liver function test increased 1 (2.2) 0 0 0 0 0 Protein urine present 0 0 0 0 0 1 (5.6) Infections and infestations 1 (2.2) 0 1 (5.6) 0 1 (5.6) Cellulitis 0 0 0 0 1 (5.6) 0 Nasopharyngitis 1 (2.2) 0 0 0 0 0 Urinary tract infection 0 0 1 (5.6) 0 0 0 Cardiac disorders 0 0 0 0 1 (5.6) 0 Bradycardia 0 0 0 0 1 (5.6) 0 Musculoskeletal and connective tissue disorders 0 0 0 1 (5.6) 0 0 Pain in extremity 0 0 0 1 (5.6) 0 0

TABLE 22 Summary of Adverse Events (Safety Population) Dose groups Placebo 20 μg 60 μg 80 μg 120 μg 180 μg Category, n (%) (N = 45) (N = 18) (N = 18) (N = 18) (N = 18) (N = 18) Any TEAE 10 (22.2) 5 (27.8) 6 (33.3) 10 (55.6) 12 (66.7) 12 (66.7) Any treatment related TEAE 10 (22.2) 4 (22.2) 5 (27.8) 10 (55.6) 10 (55.6) 11 (61.1) TEAE severity Mild 8 (17.8) 5 (27.8) 5 (27.8) 9 (50.0) 11 (61.1) 7 (38.9) Moderate 2 (4.4) 0 1 (5.6) 1 (5.6) 1 (5.6) 5 (27.8) Severe 0 0 0 0 0 0 Any SAE 0 0 0 0 0 0 Any AE leading to discontinuation 0 0 0 0 0 0 Abbreviations: AE = adverse events; TEAE = treatment-emergent adverse event; SAE = serious adverse event Percentages are based on the number of Safety Population subjects in each treatment arm. If a subject experienced more than one adverse event in a category, the subject is counted only once in that category.

Conclusion: Dexmedetomidine sublingual film treatment significantly improved the severity of agitation from baseline as measured by PEC, CGI-I, and ACES scales in schizophrenia patients. The primary efficacy endpoint was met in 80 μg, 120 μg, and 180 μg treatment groups as there was significant improvements in PEC total scores from baseline at 2 hours post-dose with mean changes of −7.3, −9.2, and −10.8 points, respectively, versus −4.5 for placebo. LSM differences from placebo were −2.9 (P=0.0210), −4.6 (P=0.0003), and −6.3 (P<0.0001) for the 80 μg, 120 μg, and 180 μg groups, compared with placebo The proportion of responders (ie, a ≥40% decrease in PEC total score) at 2 hours post-dose was significantly higher in the 120 μg and 180 μg dose groups (68.8% [P=0.0158]) and 94.4% [P<0.0001], respectively) compared with placebo (31.0%). Further, changes in secondary efficacy measures (ie, CGI-I and ACES scores) at 2 hours post-dose were consistent with the results for PEC total scores and were indicative of improvement in symptoms of agitation after treatment with Dexmedetomidine sublingual film.

Example 4: Phase 1, Randomized, Single-Blind, Placebo-Controlled, Single Ascending Dose Study of the Pharmacokinetics, Safety & Tolerability of Dexmedetomidine Sublingual Film (Example 1 Formulation) in Healthy Adult Volunteers

This was a randomized, single-blind, placebo-controlled, single ascending dose pharmacokinetics, safety and tolerability study with 4 dosing groups in healthy adult (18-65 years-old) males and females. The study protocol was reviewed and approved by an institutional review board of site(s). This study was conducted in accordance with the Declaration of Helsinki and ICH-Good Clinical Practices (GCP).

Primary Objective: Determine the PK, safety and tolerability of the various film strengths of dexmedetomidine sublingual film for identification of appropriate film dosage strengths to be carried forward into subsequent clinical trials.

Secondary Objectives:

-   -   1. Determine the PD effects of the various film strengths of         dexmedetomidine sublingual film.     -   2. Determine the relationship between PD effects and plasma         concentrations of the dexmedetomidine.     -   3. Determine the time to onset of drowsiness after         dexmedetomidine sublingual film administration.     -   4. Determine the length of sedative effect after dexmedetomidine         sublingual film administration.     -   5. Determine the approximate dissolution time of dexmedetomidine         sublingual films in the SL space.     -   6. Determine local irritation that may be caused by         dexmedetomidine sublingual film.

Endpoints

Primary

Pharmacokinetics

-   -   1. Area under the curve (AUC0-12, AUC0-24, AUC0-inf) for 0 to 12         hours and 0 to 24 hours post dosing for dexmedetomidine plasma         concentration.     -   2. Determine peak plasma dexmedetomidine concentration (Cmax).     -   3. Determine time corresponding to peak dexmedetomidine         concentration level (Tmax).     -   4. Determine terminal half-life (t1/2) of dexmedetomidine from         the central compartment.     -   5. Determine the volume of distribution (Vz) of dexmedetomidine.     -   6. Determine the clearance of dexmedetomidine (CL) from the         central compartment.

Safety and Tolerability

-   -   1. Determine electrocardiogram (ECG) and vital sign         abnormalities including adverse effects on blood pressure (BP),         heart rate, or respirations with various film strengths of         dexmedetomidine sublingual film.     -   2. Determine abnormal laboratory values following administration         of dexmedetomidine sublingual film.     -   3. Determine changes in physical examination following         administration of dexmedetomidine sublingual film     -   4. Number of subjects experiencing an AE up to Day 14 following         dexmedetomidine sublingual film administration.     -   5. Number of subjects who discontinued study treatment or         removed SL films due to an AE or other reason.     -   6. The degree to which AEs can be tolerated by assessing the         number of subjects requiring:         -   Hemodynamic interventions for maintaining BP;         -   Cardiac interventions for maintaining heart rate;         -   Respiratory interventions for maintaining oxygen saturation.

Secondary

-   -   1. The sedative effect assessed by RASS and Visual analogue         scales/sedation (VAS/S) on day of dexmedetomidine sublingual         film dosing.     -   2. Time in minutes and seconds from administration of         dexmedetomidine sublingual film until RASS of −1 on day of         dexmedetomidine sublingual film dosing.     -   3. Time in minutes and seconds from RASS of −1 till resolution         of drowsiness on day of dexmedetomidine sublingual film dosing.     -   4. Time in minutes and seconds from SL administration of         dexmedetomidine sublingual film till its complete dissolution or         up to 30 minutes.

Study design: It was a randomized, single-blind, placebo controlled, single ascending dose PK, safety and tolerability study conducted in healthy adult (18-65-year-old) males and females. The study evaluated increasing doses of dexmedetomidine sublingual film in 4 cohorts of healthy adult participants.

Four (4) doses were evaluated derived from three film strengths of 10 μg, 40 μg, and 60 μg: 10 μg, 20 μg (2×10 μg film), 40 μg, and 60 μg in Cohort 1, 2, 3 and 4 respectively. During the review of the safety and tolerability data from Cohort 3 dosing (40 μg), it was observed that 6 symptomatic subjects had reported dizziness upon standing, four of whom had concomitant intermittent hypotension or bradycardia (SBP/DBP/heart rate with >30 mmHg decrease from baseline, SBP <90 or DBP <60 or heart rate <50). While the results remained blinded, it was decided to decrease the planned dose for Cohort 4 to 40 μg. The actual doses administered to subjects in this study included 10 μg (cohort 1), 20 μg (cohort 2) and 40 μg (cohorts 3 and 4).

All eligible participants, who have been previously screened, arrived at the clinical research unit (CRU) a day before for admission and baseline assessment. They were domiciled in the CRU for 4 days (Day −1, 1, 2 and 3) and discharged on Day 4, and were under medical supervision during this time. The pre-dose evaluation of all the participants was done approximately between 07:00 and 09:00 hours, after an overnight fast of at least 8 hours. The participants were given free access to drinking water until at least one hour before dosing. A venous catheter was inserted for allowing sampling for PK. At the beginning of each study session, a single dose of dexmedetomidine sublingual film (Example 1) was administered sublingually by an unblinded staff. The dexmedetomidine sublingual film was retained in the sublingual cavity until dissolved. Evaluations were done every 5 minutes for the first 15 minutes and then every 15 minutes to determine the time to dissolution of the film. Subjects were also evaluated for local irritation around the area where the film was placed. The subjects were not allowed to sit or stand up during the first 2 hours after dexmedetomidine sublingual film dosing, except when performing standing BP measurements. After 2 hours, the subjects were allowed to sit in their beds, however, during sampling, they had to rest in supine or semi-recumbent position. The ECG, BP and oxygen saturation were monitored as per the schedule (Table 23). Subjects were allowed water as desired at least 1 hour after drug administration. Standard meals were offered at approximately 4, 8, and 12 hours after dexmedetomidine sublingual film dosing. However, no food or drinks were permitted until an investigator confirms that each subject was capable of oral intake, based on the degree of sedation and ability to control urination. Lavatory visits were also allowed, but along with an attendant. Day 2 and 3 had no dietary restriction, but there was complete restriction on smoking and alcohol intake during the length of CRU stay. After plasma sampling for 24 hours following dosing of dexmedetomidine sublingual film, the safety and tolerability assessments were continued until the morning of Day 4 (day of discharge), and were repeated on Day 5, Day 7±1 and Day 14±2.

Number of Subjects:

The study evaluated increasing doses of dexmedetomidine sublingual film (example 1—formulation) in 4 cohorts of healthy adult subjects. In the first two cohorts (Cohort 1 and Cohort 2), twelve (12) new subjects were enrolled per cohort, randomized in a ratio of 2:1, i.e. 8 receiving dexmedetomidine sublingual film and 4 receiving Placebo film.

Subjects receiving active drug in Cohort 1/Cohort 2 were to be escalated to receive high dose of active drug in Cohort 3/Cohort 4 and subjects receiving Placebo in Cohort 1/Cohort 2 were to receive Placebo in Cohort 3/Cohort 4 respectively. Six new subjects were to be randomized to receive the active drug in Cohort 3/Cohort 4. Dose-proportionality and dose-exposure response were to be evaluated in the subjects that crossed over to Cohort 3/Cohort 4. The effect of dexmedetomidine sublingual film on BP, heart rate, RASS score, other AEs and PK parameters were to be evaluated in new subjects who were not previously exposed to dexmedetomidine sublingual films. In case of placebo dropouts, while escalating from Cohort 1 to Cohort 3 or Cohort 2 to Cohort 4, additional new subjects were to be randomized to make up the total subjects to 4 subjects in Placebo arm of Cohort 3 and Cohort 4.

Day −1 Day 2 & 3 Day 4 Day 14 ± 2 (Admission; Day 1 (Observation in (At time of Day 5 Day 7 ± 1 (Visit 4, Activity Screen Visit 1) (Study drug dosing)¹ CRU) discharge) (Visit 2)⁴ (Visit 3)⁴ EOS)⁴ Informed Consent Form X Demographics X Medical History X X Weight/Body Mass Index X X X X X X Height X Inclusion/Exclusion X X X criteria Randomization X Safety Labs X X X (Chemistry, hematology, U/A, UDS² were done by the unit's local lab) Pregnancy test (Blood X HCG) Pregnancy test (Urine X HCG) Coagulation (PT/INR) X Physical Exam X X X X X X X Complete Neurological X X Exam Brief Neurological Exam X X (at resolution of drowsiness after drug administration) Vital signs (systolic and X X 0 (predose), 10, 20 and 30 X X X X X diastolic blood pressure, min, then every 15 min till pulse rate, respiration and 6 hours. Thereafter prior to oxygen saturation) PK samples (if any) (±15min) or hourly until time of sleep and again with last sample at 24-hour (±15min). Standing blood pressure X (at night) X (−2 hours predose, 2, 4, X X 6 hours postdose) ECG X X Every 3 hours (from 0 until X X X X X 6 hours postdose (±15min). Admit to Unit X Study Drug Preparation X (unblinded pharmacist) Venous Catheter X Placement Study drug Sublingually Film buccal dissolution X Buccal/Sublingual Exam X X X (at every hour starting X X X X X for local irritation from predose until time of sleep and again with last sample at 24-hour (±15min). RASS³ X 0 min, every 5 min until drowsiness is achieved (RASS of −1); then every 15 min until resolution of drowsiness Prior to PK sample collection, till resolution of drowsiness VAS/S 0 min, every 30 min until resolution of drowsiness Prior to PK sample collection (±5min) Training X PK Sampling As per sampling schedule Discharge X Concomitant Meds X X X X X X X X Adverse Events X X X X X X X X ECG: electrocardiogram; hCG: human chorionic gonadotropin; PK: pharmacokinetic; PT/INR: prothrombin time/ international normalized radio; RASS Richmond Agitation Sedation Scale; U/A: Urine Analysis; UDS: Urinary Drug Screen; VAS/S: visual analogue scales/sedation ¹Predose assessments had a window of 60 min prior to drug administration. ²UDS was not done at the discharge day ³If a subject did not achieve drowsiness (RASS of -1) on or before the 90 minute postdoc timepoint, the procedure was to be performed at 5 minute increments until 90 minutes postdose, then at 15-minute increments until 120 minutes postdose. RASS had a 3 minute window period. ⁴Any abnormal vital sign measurement, clinical laboratory test, physical examination finding, or ECG parameter deemed clinically significant by the investigator was to be repeated, inculding test results obtained on the final single-blind study day or upon early termination. For any test abnormality deemed clinically significant, repeat analysis was to be performed during the follow-up period and until the value returned to baseline (or within normal limits) or the investigator deemed the abnormality to be of no clinical significance.

Inclusion Criteria:

-   -   1. Healthy males and non-pregnant/non-breast-feeding females         between 18 and 65 years of age, both inclusive.     -   2. Subjects who were capable of giving written informed consent         for the study     -   3. Subjects that had body weight ≥50 kg with body mass index         (BMI) in the range of 19-30 kg/m2, both inclusive     -   4. Subjects having physical examination and vital signs judged         to be within normal limits by the PI or designee.     -   5. Subjects whose clinical laboratory tests (complete blood         count, blood chemistry, and urinalysis) were within normal         limits or are clinically acceptable to the PI or designee.     -   6. Subjects who were sufficiently physically healthy to receive         a SL dose strength of dexmedetomidine sublingual film, and         tolerate drowsiness, in the opinion of the PI or designee.     -   7 Subjects who were fluent in English and have ability to         understand written and verbal protocol-related requirements in         English.     -   8. Subjects who were willing and able to be confined to the CRU         for approximately 4-5 days per dosing cohort and comply with the         study schedule and study requirements.     -   9. Subjects that had reliable intravascular access from which to         draw blood samples.     -   10. Male subjects, if non-vasectomized, must agree to use a         condom with spermicide or abstain from sexual intercourse,         during the trial and for 3 months after stopping the medication.     -   11. Male subject must not donate sperm starting at screening and         throughout the study period, and for 90 days after the final         study drug administration.     -   12. For female subjects of child-bearing potential, the subject         must be willing to practice a clinically accepted method of         birth control from at least 30 days prior to the first         administration of the study medication, during the study, and         for at least 30 days after the last dose of the study         medication.     -   13. For female of non-childbearing potential, the subject was         surgically sterile (i.e. has undergone hysterectomy, bilateral         oophorectomy, or tubal ligation) or in a menopausal state (at         least 1 year without menses), as confirmed by Follicle         stimulating hormone (FSH) levels.

Exclusion Criteria:

-   -   1 The subjects with a history of allergic reaction or         intolerance to the study drug or related compounds and         additives.     -   2. The subjects with a history of major surgery within 4 weeks         of screening.     -   3. The subjects with a history of significant traumatic brain         injury.     -   4. The subjects with a history of alcohol or drug dependence by         Diagnostic and Statistical Manual of Mental Disorders IV         criteria during the 6-month period prior to study entry.     -   5. The subjects with a history of or presence of clinically         significant psychiatric illnesses mental retardation, borderline         personality disorder, anxiety disorder, or organic brain         syndrome.     -   6. The subjects with a history of orthostatic hypotension (i.e.,         a sustained reduction of systolic BP (SBP) of at least 20 mmHg         or diastolic BP (DBP) of 10 mmHg, or both, within 3 min of         standing or head-up tilt to at least 60° on a tilt table) and         high vagal tone.     -   7 The subjects who regularly consume large amounts of         xanthine-containing substances (i.e., more than 5 cups of coffee         or equivalent amounts of xanthine-containing substances per         day).     -   8. The subjects who were on maintenance medications that could         inhibit or induce the CYP2A6 enzyme.     -   9. The subjects who had received dexmedetomidine or other         alpha-2-agonists within 1 week of the study date.     -   10. The subjects who had clinically significant sleep apnea or         chronic obstructive pulmonary disease or history of asthma.     -   11. The subjects with suicidal tendency in the judgement of the         PI or designee.     -   12. The subjects with clinical laboratory abnormalities         (including positivity for Hep B, Hep C, HIV) unless treated to         remission status.     -   13. The subjects with abnormal vital signs measurement in the         judgement of the PI or designee, unless treated to remission         status.     -   14. The subjects those were enrolled in another clinical study         (e.g., laboratory or clinical evaluation) or have received an         investigational drug in the past 30 days (or within 5 half-lives         of the investigational drug, if >30 days).     -   15. The subjects that had a resting heart rate of <65 beats per         minute or SBP <110 mmHg or >140 mmHg or DBP <70 mmHg or >100         mmHg at screening and pre-dosing. Have evidence of a clinically         significant 12 lead ECG abnormality. Subjects that previously         failed eligibility criteria at the Screening visit or Day 1         predose due to Exclusion 15 for a resting heart rate <70 beats         per minute but not <65 beats per minute may be rescreened.     -   16. The subjects with an aberrant oral/buccal anatomy,         inflammation or pathology which in the opinion of the PI, may         affect SL drug administration and absorption.     -   17. The subjects with hepatic impairment or who have hepatic         dysfunction defined as a history of hepatic dysfunction and an         Alanine Aminotransferase (ALT) and Aspartate Aminotransferase         (AST) values greater than 2 times normal in the past 6 months         prior to study drug administration.     -   18. The subjects who had donated blood within 30 days prior to         screening or plasma donation within 7 days prior to screening.     -   19. The subject who was part of the study staff personnel or         family members of the study staff personnel.

Study duration: 39-42 days.

Treatments Administered

The following treatments were administered on Day 1: Active: Dexmedetomidine hydrochloride SL film at dose levels of 10 μg (1×10 μg film), 20 μg (2×10 μg films) and 40 μg (1×40 μg film)

Placebo: Placebo SL film

Cohort 1 and Cohort 2 were given 10 μg and 20 μg (2×10 μg films), respectively, Cohort 3 and Cohort 4 received 40 μg of dexmedetomidine sublingual film. All Cohorts were given accompanying Placebo. Except for the first dose cohort (10 μg dose), each subsequent dose level was authorized after safety review of the previous dosing cohort. Dexmedetomidine hydrochloride sublingual film (having dot) was different from Placebo in appearance.

Results:

Data Sets Analyzed

Safety Population

The safety population includes all randomized subjects who received at least 1 dose of single-blind study drug (n=42).

Pharmacokinetic Population

The PK population includes 28 subjects receiving dexmedetomidine sublingual film. Fourteen subjects who received placebo were not included in the PK analysis. For the subjects receiving placebo only visual analogue scale/sedation (VAS/S), Richmond Agitation-Sedation Scale (RASS), and vital signs (diastolic blood pressure, systolic blood pressure, pulse rate, respiratory rate, and oxygen saturation) versus time plots were provided.

Pharmacodynamic Population

The PD population includes all randomized subjects who received at least 1 dose of single-blind study drug and had post-baseline PD assessments performed (n=42).

Demographic and Other Baseline Characteristics

Overall, the majority of healthy subjects participating in the study (59.5%) were white (non-Hispanic or Latino), a smaller proportion (31.8%) were black (African American). There was 1 (2.4%) Hispanic or Latino subject and 1 (2.4%) Asian subject in the study.

Overall, the number of male and female subjects in the study was comparable: 22 (52.4%) of all subjects were male and 20 (47.6%) were female. The mean age was 44.8 years; the subjects ranged in age from 20 to 65 years; 22 (52.4%) subjects were between 20 and 49 years and 20 (47.6%) subjects were between >49 and 65 years.

The majority of the subjects in the Placebo group were male (64.3%). Among the subjects administered dexmedetomidine sublingual film, the proportion of male (46.4%) and female (53.6%) subjects was comparable.

The physical measurements in the placebo and dexmedetomidine sublingual film group were comparable as well: a mean body mass index (BMI) was 25.50 kg/m² in the subjects administered dexmedetomidine sublingual film and 25.83 kg/m² in the Placebo group.

Pharmacokinetic results: Dexmedetomidine was rapidly absorbed with measurable concentrations observed at 10 minutes for all dose levels and until 8 hours postdose for the 10 μg dose levels and until 10 and 12 hours postdose for 20 μg and 40 μg dose levels, respectively, with a short mean t_(1/2) that ranged between 1.82-2.16 h. Mean±SD DEX plasma concentrations-time profiles at each dose (semi-log scale) plotted against sampling time until 8 hrs postdose are presented in FIG. 8 . Dose proportionality assessment indicated that Cmax and AUCs increased in a dose-proportional manner with mean Cmax ranged between 29.21 and 122.84 ng/L and mean AUC_(0-inf) ranged between 130.62 and 561.57 hr·ng/L. Similar trends were seen with AUC_(last) and AUC₀₋₂₄ (Tables 30 to 32; FIGS. 9A to 9C)).

TABLE 24 summarizes pharmacokinetics parameters of 10 micrograms dexmedetomidine sublingual film in healthy volunteers 10 μg dexmedetomidine sublingual film C_(max) T_(max) t_(1/2) AUC_(last) AUC_(0-INF) Subject ID (ng/L) (hr) (hr) (hr*ng/L) (hr*ng/L) 1001 37.94 1.5 2.06 179.19 201.32 1002 18.27 1.00 1.17 49.45 58.27 1005 33.28 2.00 1.86 116.63 140.07 1007 35.74 2.00 2.95 142.22 168.59 1009 24.15 3.02 2.70 102.76 1011 30.87 1.00 2.75 114.35 138.82 1012 24.53 1.50 2.58 98.28 1016 35.19 2.00 1.24 119.28 129.17 N 8 8 8 8 6 Mean 30 1.752 2.163 115.271 139.37 SD 6.930 0.66 0.693 37.05 47.69 CV % 23.1 37.62 32.0 32.1 34.22 Min 18.27 1.00 1.17 49.45 58.27 Median 32.08 1.75 2.32 115.49 139.45 Max 37.94 3.02 2.95 179.19 201.32 Geometric 29.214 1.65 2.051 109.22 130.62 Mean Geometric 25.79 39.08 37.61 38.59 44.75 CV %

TABLE 25 summarizes pharmacokinetics parameters of 20 micrograms dexmedetomidine sublingual film in healthy volunteers 20 μg dexmedetomidine sublingual film C_(max) T_(max) t_(1/2) AUC_(last) AUC_(0-INF) Subject ID (ng/L) (hr) (hr) (hr*ng/L) (hr*ng/L) 2001 0.00 0.00 0.00 2003 83.08 1.00 2.2 359.59 389.48 2004 65.17 2.00 1.72 259.50 279.49 2007 84.90 1.50 1.60 401.79 416.92 2011 70.76 2.00 1.85 309.75 337.01 2013 85.92 1.00 1.85 307.97 330.48 2016 42.34 3.00 1.97 198.79 225.81 2106 66.75 1.50 1.57 283.34 301.60 N 8 7 7 8 8 Mean 62.37 1.71 1.824 265.092 285.10 SD 28.982 0.70 0.221 123.337 129.91 CV % 46.47 40.75 12.1 46.5 45.57 Min 0.00 1.00 1.57 0.00 0.00 Median 68.76 1.50 1.85 295.66 316.04 Max 85.92 3.00 2.20 401.79 416.92 Geometric — 1.601 1.813 — — Mean Geometric — 41.30 11.95 — — CV %

TABLE 26 summarizes pharmacokinetics parameters of 40 μg dexmedetomidine sublingual film in healthy volunteers 40 μg dexmedetomidine sublingual film C_(max) T_(max) t_(1/2) AUC_(last) AUC_(0-INF) Subject ID (ng/L) (hr) (hr) (hr*ng/L) (hr*ng/L) 3011 140.25 1.00 1.78 685.15 709.61 3012 78.69 2.00 2.00 427.97 461.18 3013 97.01 1.07 1.76 292.84 310.29 3023 126.60 1.00 1.86 493.89 508.98 3026 135.02 1.50 1.38 482.44 499.41 3032 78.06 2.00 378.67 3114 167.99 1.00 2.05 777.66 806.08 3131 123.52 2.02 2.42 600.88 627.60 4001 109.62 1.00 1.82 419.51 446.40 4022 204.03 1.00 1.82 664.47 704.50 4026 123.68 2.00 1.83 507.83 534.00 4130 143.95 2.00 1.97 772.97 798.78 N 12 12 11 12 11 Mean 127.37 1.47 1.88 542.02 582.24 SD 35.79 0.49 0.25 157.144 158.70 CV % 28.10 33.75 13.44 28.99 27.25 Min 78.06 1.00 1.38 292.84 310.29 Median 125.14 1.28 1.83 500.86 534.00 Max 204.03 2.02 2.42 777.66 806.08 Geometric 122.84 1.39 1.87 520.58 561.57 Mean Geometric 28.87 35.22 13.7 30.84 29.65 CV %

Pharmacodynamic Results:

The sedative effect of dexmedetomidine sublingual film was assessed by RASS and Visual analogue scales/sedation (VAS/S) on day of dexmedetomidine sublingual film dosing. The assessment included:

-   -   Time in minutes and seconds from administration of         dexmedetomidine sublingual film until RASS of −1;     -   Time in minutes and seconds from RASS of −1 till resolution of         drowsiness;     -   Time in minutes and seconds from SL administration of         dexmedetomidine sublingual film till its complete dissolution or         30 minutes.     -   Richmond Agitation Sedation Scale

All RASS scores assessed during the study ranged between −2 (Light Sedation) and 0 (Alert and Calm). The baseline score for all subjects was 0 (Alert and Calm). Overall, a total of 14 subjects achieved drowsiness (RASS of −1) across all treatments. Of these, 2 received 10 μg dose group, 4 received 20 μg dose group, 5 received 40 μg dose group, and 3 received Placebo. Two subjects also achieved light sedation (RASS of −2), 1 received 10 μg dose group and the other one received Placebo.

The mean times to achieve drowsiness from baseline for subjects administered dexmedetomidine sublingual film and placebo is summarized in Table 33. Overall, the time to achieve drowsiness was variable across all treatment groups and ranged from 19 minutes to 85 minutes in dexmedetomidine sublingual film groups and from 19 minutes 17 seconds to 107 minutes 29 seconds in placebo group. No statistically significant between-group differences were observed for either 10 μg or 40 μg treatment groups.

The duration from onset of drowsiness (RASS of −1) until resolution for subjects administered dexmedetomidine sublingual film and Placebo is summarized in Table 34. Overall, the duration from onset of drowsiness (RASS of −1) until resolution was variable across all treatment groups and ranged from 05 minutes 05 seconds to 91 minutes. Mean duration in subjects administered dexmedetomidine sublingual film was 48 minutes 24 seconds, and subjects administered placebo presented a mean duration of 37 minutes 25 seconds.

TABLE 27 Achievement of Drowsiness (in minutes: seconds) from Baseline Assessed by RASS of −1 Dexmedetomidine sublingual film Cohort 2 Cohort 4 Cohort 1 (10 μg) (20 μg) Cohort 3 (40 μg) (40 μg) Cohort 3 + 4 (40 μg) Active Placebo Active Active Placebo Active Active Placebo Statistics (N = 8) (N = 4) (N = 8) (N = 8) (N = 4) (N = 4) (N = 12) (N = 6) n 2 2 4 3 1 2 5 1 Mean (SD) 31:30 65:47 59:16 47:30 19:17 24:00 38:60 19:17 (3:32) (58:58) (18:16) (10:27) (7:40) (15:15) Median 31:30 65:47 54:20 44:20 19:17 24:00 39:00 19:17 Min, Max 29:00, 24:50, 44:00, 39:00, 19:17, 19:00, 19:00, 19:17, 34:00 107:29 85:00 59:10 19:17 29:00 59:10 19:17 P-value vs 1.000 0.5000 0.6667 Placeboa ^(a)P-value is based on a non-parametric two-sided (exact) Wilcoxon test. n-number of subjects who have reached at least RASS of −1 at any time in the first 2 hours

TABLE 28 Duration from RASS of −1 till Resolution of Drowsiness (in minutes:seconds) Dexmedetomidine sublingual film Cohort Cohort Cohort Cohort Cohort 3 and 4 1 10 μg 2 20 μg 3 40 μg 4 40 μg 40 μg Overall Pooled Statistics (N = 8) (N = 8) (N = 8) (N = 4) (N = 12) Active^(a)(N = 28) Placebo^(a)(N = 14) Overall^(a)(N = 42) n 2 4 3 2 5 11 2 13 Mean 84:30 53:49 28:00 32:03 29:37 48:24 (28:45) 37:25 (10:38) 46:43 (26:44) (SD) (9:12) (10:56) (30:29) (38:07) (28:52) Median 84:30 52:39 15:01 32:03 15:01 59:00 37:25 45:12 Min, Max 78:00, 44:00, 6:10, 5:05, 5:05, 5:05, 91:00 29:54, 44:56 5:05, 91:00 91:00 66:00 62:50 59:00 62:50 ^(a)Overall Active, Pooled Placebo and Overall columns include assessment counts not subject level counts. n - number of subjects who have reached at least RASS of −1 at any time in the first 2 hours

Visual Analogue Scales/Sedation:

The subjective sedative effect of dexmedetomidine was assessed by means of VAS. Subjects were asked to score their feeling on a 100-mm horizontal scale, with 0 indicating very sleepy and 100 indicating very alert. Overall, VAS scores were variable with the lowest scores being generally observed at the 1.0 and 1.5-hour timepoints for subjects dosed with dexmedetomidine sublingual film. Mean scores observed at pre-dose 0.5, 1, 1.5- and 2-hours following treatment with dexmedetomidine sublingual film or placebo and P-values are presented in Table 29 and FIG. 10 . There were no statistically significant between-group differences (Active vs. Placebo) observed in Cohorts 1 (10 μg), Cohort 2 (20 μg) and Cohorts 3 and 4 combined (40 μg dose). Statistically significant differences were only seen in Cohort 3 (40 μg). However, the statistical significance in this cohort was also reported for the pre-dose assessment (P<0.05; Table 29) indicating that the study environments and score variability may have affected the outcome.

Dexmedetomidine Sublingual Film Dissolution Time:

A single dose of dexmedetomidine sublingual film was administered sublingually. For 20 μg dose cohort, two (2) 10 μg films were administered simultaneously. The drug film was retained in the sublingual cavity until it had dissolved. There was an evaluation every 5 minutes for the first 15 minutes, and then every 15 minutes to determine the time to dissolution of the film. Mean, median, and min and max dissolution time for each treatment group in minutes:seconds are presented in Table 30. Overall, duration from the SL administration of dexmedetomidine sublingual film or Placebo film until its complete dissolution was variable and ranged from 3 minutes to 44 minutes 11 second. Mean (SD) and median dissolution times were similar for dexmedetomidine sublingual film (14:09 (11:33); 11:11, minutes: seconds) and Placebo (13:32 (12:49); 8:28, minutes: seconds) films. No subject presented aberrant oral/buccal anatomy or inflammation during the buccal mucosal irritation examination.

Safety Evaluation:

Based on the results in this study, the following safety conclusions can be made:

-   -   There were no deaths or serious TEAEs reported in the study. One         subject administered dexmedetomidine sublingual film 10-μg had a         decrease in heart rate >30 beats per minute (withdrawal         criterion) therefore had become ineligible to participate in         Cohort 3. An overall summary of AEs is provided in Table 31. A         total of 52 TEAEs were reported by 25 of the 28 subjects (89%)         administered dexmedetomidine sublingual film and 20 TEAEs were         reported by 10 of the 14 subjects (71%) administered placebo.         All TEAEs were recovered by the end of the study.

Subjects administered dexmedetomidine sublingual film reported TEAEs with an incidence of 75% for 10 μg dose group, 88% for 20 μg dose group and 100% for 40 μg dose group. Drug-related TEAEs were reported with an incidence of 75% following administration of 10 μg dose group, 88% following administration of 20 μg dose group, 92% following administration of 40 μg dose group and 64% following administration of placebo.

The most experienced TEAE during the study was somnolence, which was reported with a slightly higher frequency at doses of 20 μg and 40 μg (75% each) compared to the 10 μg dose and placebo (50% each) (Table 32). The majority of TEAEs were mild in severity in all treatment groups with only few moderate TEAEs reported. Moderate TEAEs were experienced following administration of 10 μg dose (1/12; 8%), 40 μg dose (2/30; 7%) and administration of placebo (4/20; 20%). No severe TEAEs were reported in this study.

No subject dosed in this study required hemodynamic/medical interventions for maintaining BP, cardiac interventions for maintaining heart rate or respiratory interventions for maintaining oxygen saturation. No subject was withdrawn due to a TEAE. The data is further depicted in FIGS. 11 to 15 .

-   -   Two subjects presented symptomatic changes in vital signs that         were considered clinically significant and reported as vital         signs related TEAEs. One subject administered placebo had a         decrease in DBP and SBP that were recorded as drug-related TEAEs         of moderate and mild intensity, respectively and 1 subject         administered 40 μg dose group had decreases in heart rate that         were recorded as 2 drug-related TEAEs of mild intensity. All         TEAEs were resolved within 1 day from onset.     -   There were no clinically significant changes in laboratory         parameters and ECG assessments. No physical examination finding         was considered clinically significant by the investigator. All         neurological examinations performed during the study were normal         and no subject presented aberrant oral/buccal anatomy or         inflammation during the buccal mucosal irritation examination.

TABLE 29 Summary of Visual Analogue Scales/Sedation Cohort 1 Cohort 2 Cohort 3 (10 μg) (20 μg) (40 μg) Time Active Placebo Active Placebo Active Placebo point Statistics (N = 8) (N = 4) (N = 8) (N = 4) (N = 8) (N = 4) Pre- n 8 4 8 4 8 4 dose Mean 95.5 97.8 97.4 86.5 74.8 100 (SD) (12.73) (4.50) (6.25) (21.30) (35.29) (0.00) P-value 1 0.2384 0.0485* 0.5 n 8 4 8 4 8 4 Hour Mean 78.8 90.0 74.4 55.8 73.0 93.0 (SD) (23.50) (11.52) (20.87) (35.61) (25.72) (12.68) P-value 0.4788 0.2788 0.0465* 1.0 n 5 4 8 4 8 4 Hour Mean 67.6 93.8 43.0 48.5 42.8 94.3 (SD) (33.30) (6.65) (38.26) (48.50) (32.98) (10.18) P-value 0.3175 0.9737 0.0121* 1.5 n 8 4 8 4 7 3 Hour Mean 63.0 80.3 43.8 53.5 53.0 99.7 SD (29.69) (30.18) (40.02) (48.64) (41.68) (0.58) P-value 0.4586 0.4869 0.0167* 2.0 n 8 4 8 4 7 3 Hour Mean 81.8 74.5 54.9 59.0 50.9 99.7 (SD) (25.97) (42.19) (38.92) (47.79) (36.22) (0.58) P-value 0.9253 0.8848 0.0167* Cohort Cohort 4 3 + 4 (40 μg) (40 μg) Time Active Placebo Active Placebo Overall point Statistics (N = 4) (N = 2) (N = 12) (N = 6) (N = 42) Pre- n 4 2 12 6 60 dose Mean 86.8 70.5 8. 90.2 87.5 (SD) (25.84) (41.72) (31.78) (24.09) (24.18) P-value 0.8 0.139 0.5 n 4 2 12 6 60 Hour Mean 75.0 64.5 73.7 83.5 76.3 (SD) (22.67) (48.79) (23.71) (28.09) (24.24) P-value 0.8 0.2203 1.0 n 4 2 12 6 57 Hour Mean 71.5 64.0 52.3 84.2 61.7 (SD) (22.61) (49.50) (32.13) (28.22) (34.97) P-value 0.8 0.0691 1.5 n 4 2 11 5 56 Hour Mean 78.8 70.0 62.4 87.8 65.0 SD (25.59) (42.43) (37.52) (26.72) (36.06) P-value 0.9333 0.0627 2.0 n 3 2 10 5 54 Hour Mean 73.0 72.5 57.5 88.8 67.9 (SD) (24.88) (37.48) (33.56) (23.93) (34.28) P-value 0.8 0.0513 P-Values are calculated for Active vs Placebo for each cohort. P-value based on non-parametric two-sided (exact) Wilcoxon test. *Statistically significant between-group difference (Active vs Placebo)

TABLE 30 Duration from SL Administration (in minutes:seconds) of Dexmedetomidine sublingual film till its Complete Dissolution (PD Population) Dexmedetomidine sublingual film Cohort 3 and Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 4 Pooled 10 μg 20 μg 40 μg 40 μg 40 μg Overall Active* Placebo* Overall* Statistics (N = 8) (N = 8) (N = 8) (N = 4) (N = 12) (N = 28) (N = 14) (N = 42) n 8 8 8 4 12 28 13 41 Mean (SD) 9:03 (7:52) 23:49 (12:36) 14:26 (10:04) 4:26 (2:24) 11:06 (9:30) 14:09 (11:33) 13:32 (12:49) 13:58 (11:49) Median 5:11 29:01 14:05 3:23 8:09 11:11 8:28 8:28 Min, Max 3:00, 24:30 8:00, 44:01 3:18, 29:01 3:00, 8:00 3:00, 29:01 3:00, 44:01 3:00, 44:11 3:00, 44:11 *Overall Active, Pooled Placebo and Overall columns include assessment counts not subject level counts.

TABLE 31 Summary of Adverse Events Dexmedetomidine sublingual film Cohort 3 and Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 4 10 μg 20 μg 40 μg 40 μg 40 μg Overall Placebo Overall (N = 8) (N = 8) (N = 8) (N = 4) (N = 12) (N = 28) (N = 14) (N = 42) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) AEs reported 75 TEAEs reported 12 10 24 6 30 52 20 72 Subjects with at 6 (75.0) 7 (87.5) 8 (100.0) 4 (100.0) 12 (100.0) 25 (89.3) 10 (71.4) 35 (83.3) least one TEAEª Subjects with at 6 (75.0) 7 (87.5) 8 (100.0) 3 (75.0) 11 (91.7) 24 (85.7)  9 (64.3) 33 (78.6) least one drug- related TEAEª TEAEs relationship^(b) Possibly related 4 (33.3) 2 (20.0)  5 (20.8) 0  5 (16.7) 11 (21.2)  4 (20.0) 15 (20.8) Probably related 2 (16.7) 0  7 (29.2) 1 (16.7)  8 (26.7) 10 (19.2)  3 (15.0) 13 (18.1) Definitely related 3 (25.0) 8 (80.0) 12 (50.0) 3 (50.0) 15 (50.0) 26 (50.0) 10 (50.0) 36 (50.0) Related 0 0 0 0 0 0  1 (5.0)  1 (1.4) Unrelated/unlikely 3 (25.0) 0 0 2 (33.3)  2 (6.7)  5 (9.6)  2 (10.0)  7 (9.7) TEAEs severity^(b) Mild 11 (91.7) 10 (100.0) 22 (91.7) 6 (100.0) 28 (93.3) 49 (94.2) 16 (80.0) 65 (90.3) Moderate  1 (8.3) 0  2 (8.3) 0  2 (6.7)  3 (5.8)  4 (20.0)  7 (9.7) Severe 0 0 0 0 0 0 0 0 STEAEs reported^(b) 0 0 0 0 0 0 0 0 Subjects with at 0 0 0 0 0 0 0 0 least one STEAE^(a) Subject with at 0 0 0 0 0 0 0 0 least one study drug-related STEAE^(a) Subjects with at 0 0 0 0 0 0 0 0 least one TEAE leading to study discontinuationa Deaths^(a) 0 0 0 0 0 0 0 0 AE: adverse event; N: number of subjects; n(%): number and percent of subjects included; SAE: serious adverse event; STEAE; serious treatment-emergent adverse event; TEAE: treatment-emergent adverse event Notes: Overall Active, Pooled Placebo and Overall columns include assessment counts not subject level counts. Possibly Related, Probably Related, Related, or Definitely Related catagories are counted under Drug-Related ^(a)Percentages are based on the number of subjects in the Safety population in each treatment group. ^(b)Percentages are based on the total number of treatment-emergent adverse events reported in each treatment group

TABLE 32 Treatment-Emergent Adverse Events Reported in Two or More Subjects Overall Dexmedetomidine sublingual film Cohort 3 and Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 4 10 μg 20 μg 40 μg 40 μg 40 μg Overall Placebo Overall System Organ Class (N = 8) (N = 8) (N = 8) (N = 4) (N = 12) (N = 28) (N = 14) (N = 42) Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Subjects with at least one 6 (75.0) 7 (87.5) 8 (100.0) 4 (100.0) 12 (100.0) 25 (89.3) 10 (71.4) 35 (83.3) TEAE Nervous system 5 (62.5) 7 (87.5) 7 (87.5) 2 (50.0) 9 (75.0) 21 (75.0)  8 (57.1) 29 (69.0) disorders Somnolence 4 (50.0) 6 (75.0) 7 (87.5) 2 (50.0) 9 (75.0) 19 (67.9)  7 (50.0) 26 (61.9) Dizziness 1 (12.5) 1 (12.5) 6 (75.0) 0 6 (50.0)  8 (28.6)  2 (14.3) 10 (23.8) Headache 1 (12.5) 1 (12.5) 0 0 0  2 (7.1)  3 (21.4)  5 (11.9) Gastrointestinal 2 (25.0) 1 (12.5) 3 (37.5) 1 (25.0) 4 (33.3)  7 (25.0)  2 (14.3)  9 (21.4) disorders Nausea 1 (12.5) 0 2 (25.0) 0 2 (16.7)  3 (10.7) 0  3 (7.1) Dry Mouth 0 0 1 (12.5) 1 (25.0) 2 (16.7)  2 (7.1)  1 (7.1)  3 (7.1) Vomiting 1 (12.5) 0 1 (12.5) 0 1 (8.3)  2 (7.1)  1 (7.1)  3 (7.1) General disorders and 1 (12.5) 0 2 (25.0) 1 (25.0) 3 (25.0)  4 (14.3)  1 (7.1)  5 (11.9) administration site conditions Fatigue 1 (12.5) 0 2 (25.0) 0 2 (16.7)  3 (10.7) 0 3 (7.1)

Conclusion: Overall, PK, PD and safety results presented in this study support further development of dexmedetomidine sublingual film for the acute treatment of agitation associated with dementia, schizophrenia, and bipolar disorders as a minimally invasive rapid-delivery dosage form of dexmedetomidine.

Example 5: Clinical Study of the Efficacy (Sedation and Anti-Agitation), Pharmacokinetics and Safety of Dexmedetomidine Infused Intravenously in Subjects Suffering from Schizophrenia

A key objective of the study was to determine the optimal intravenous (IV) dose of dexmedetomidine hydrochloride in the target population in terms of efficacy and safety to achieve arousable sedation (RASS of −1) which can be reversed by verbal stimulation. When this goal was achieved in each participant, the IV infusion of dexmedetomidine hydrochloride ceased. Another Key Objective of the study was to determine the reduction in the level of agitation, as determined by their PEC score, at the doses to achieve a RASS of −1.

In addition, the following Secondary Objectives were:

-   -   1. Determine how rapidly the drug can be administered up to the         total dose needed to achieve RASS −1.     -   2. Determine how long the calming effect persists after         discontinuation of study drug administration.     -   3. Determine whether any adverse effects on blood pressure,         heart rate, or respiratory drive occurs before or coincident         with the achievement of Primary Objective. Stopping rules for         blood pressure and heart rate, indicating a clinically         significant event, are:         -   drop in systolic BP <90 mm of Hg.         -   drop in diastolic BP <60 mm of Hg         -   drop below 50 beats per minute

Participants were provided written informed consent before any study related procedures were performed. All participants were screened for inclusion and exclusion criteria. The participants were admitted to the site at screening (Day −1), the day before the infusion. Baseline assessments were performed on Day −1, as well as on the day of infusion (Day 1). The participants were on Day 1 prepared for the infusion, infused for up to 3 hours and monitored for resolution of sedation and any decreases in blood pressure or heart rate which met stopping criteria. The participants were not discharged from the research unit until three hours after resolution of any reduction in the level of arousal (e.g., RASS −1) and/or resolution of any decrease in blood pressure or heart rate meeting stopping criteria. The Principal Investigator had discretion to keep the participant overnight at the site the evening of Day 1 for extended monitoring and then discharge home the participant on Day 2 if the Principal Investigator or designee determined that the participant has returned to their baseline state.

The study population included 14 participants, 10 active and 4 placebo. Patients 5, 7, 8 and 9 received placebo. Patients 1, 2, 3, 4, 11, 12, 14, 16, 17, 18 were infused with intravenous dexmedetomidine hydrochloride, starting at a rate of 0.2 mcg/kg/hr, and rising by 0.1 mcg/kg/hr every 30 minutes until stopping criteria were reached up or to a maximum duration of 3 hours (Table 33). Participants randomized to placebo received a matching intravenous infusion of placebo solution.

TABLE 33 Study Treatments Treatment Formulation Frequency Dexmedetomidine PRECEDEX ® Continuous infusion, hydrochloride increment every 30 minutes Placebo Normal Saline Continuous infusion

Once the participant was drowsy (RASS −1), the infusion was stopped. The maximum total dose administered was 1.6 mcg/kg/hr, when either the desired level of sedation was achieved or the maximum allowable decrease in either systolic or diastolic blood pressure or heart rate occurred.

The participants were continuously monitored during the study by the site personnel, including monitoring blood pressure and heart rate. Intermittent electrocardiograms were taken from the start of the infusion through resolution of the sedation and/or any adverse effects on blood pressure or heart rate.

Whenever the above stopping criteria was met, the site stopped the infusion and the site continued to monitor the participant's vital signs every 15 minutes until the participant has reached their baseline parameters or in the judgment of the principal investigator the participant has reached a stable and acceptable level of blood pressure and heart rate. Return to baseline parameters is defined as BP falling within 15 mm of Hg of baseline reading prior to drug administration or HR falling within 10 beats per minute of baseline reading prior to drug administration.

In the event the investigator deemed the fall in blood pressure or heart rate to be clinically significant, suitable remedial drugs could be administered in addition to termination of the dexmedetomidine hydrochloride infusion, based on investigator's judgement.

Adverse events (AEs), including serious adverse events (SAEs), were assessed, recorded, and reported in accordance with FDA guidance. Should any SAE occur, the study would be stopped until a cause for the SAE was determined.

Efficacy Assessment:

(1) Richmond Agitation Sedation Scale (RASS): The desired endpoint was how rapidly drowsiness (RASS −1) could be achieved without causing changes in heart rate or blood pressure greater than that specified by the protocol. The study also monitored how long the participant remained at that level of sedation; sedation was considered resolved when the participant was awake and spontaneously responding.

(2) PANSS: Change from baseline for mildly agitated patients

(3) Clinical Global Impression of Improvement (CGI-I) (National Institute of Mental Health 1976) ranging from 1 (very much improved) to 7 (very much worse) compared with baseline. Each participant was rated, based on the severity of agitation, at 15 and 30 minutes for every dose infusion, at the endpoint, and at the time the participant returned to baseline (in terms of level of arousal). CGI-I focused on the severity of agitation rather than the severity of the illness.

(4) After the infusion was stopped, the participants were judged for the suitability for discharge by the principal investigator or designee as witnessed by a return to their baseline level of alertness and awareness with no impairment in balance, gait, and reaction time as determined by the principal investigator or designee.

Results

(A) Efficacy Study

RASS (Richmond Agitation-Sedation Scale)

9 out of 10 patients in the treatment arm (subjects 1-3, 11, 12, 14, and 16-18) achieved a RASS score of at least −1, while no patients in the placebo arm (subjects 5, and 7-9) experienced meaningful sedation (see FIG. 16 and Table 34).

TABLE 34 Depicts the RASS score of Schizophrenia patients receiving infusion of dexmedetomidine hydrochloride and normal saline RASS values after infusion start Patient No. Infusion 1 2 3 4 5 7 8 9 11 12 14 16 17 18 (minutes) T T T T P P P P T T T T T T 0 1 3 1 1 1 1 1 1 1 1 1 1 1 0 15 −2 −1 30 0 0 0 1 1 1 0 0 0 0 0 45 0 −1 60 0 −1 0 1 1 0 1 0 0 0 0 75 1 −1 −1 −1 90 0 1 0 0 1 0 105 120 0 0 0 0 1 −1 135 0 150 0 0 0 1 165 180 0 0 0 1 T - treatment arm; P - placebo arm

PEC (PANSS Excitement Component)

9 out of 10 patients in the treatment arm (subjects 1-4, 11, 12, 14, 16 and 17) had agitation reduced to a minimum (as measured by a PEC score of 7 or below) (see Table 35 and FIG. 17 ).

TABLE 35 Depicts the PEC data of schizophrenia patients receiving infusion of dexmedetomidine and normal saline PEC values after infusion start Patient No. 1 2 3 4 5 7 8 9 11 12 14 16 17 18 Time (Mins) T T T T P P P P T T T T T T 0 9 16 12 9 11 12 9 13 13 13 10 10 10 15 5 13 12 9 10 12 9 13 13 13 9 9 8 30 12 10 8 9 9 8 12 11 13 6 6 7 45 11 7 8 9 8 8 12 9 10 6 6 5 60 9 6 7 8 8 8 13 9 10 5 7 75 7 7 8 8 7 11 7 8 5 5 90 7 7 9 7 11 6 105 7 8 8 7 10 5 120 7 8 8 7 10 135 7 8 7 7 9 150 8 7 7 9 165 8 8 7 9 180 8 8 7 10 T - treatment arm; P - placebo arm

(B) Pharmacokinetic Study: (PK Study)

The level of dexmedetomidine in the plasma of patients was also measured over the time of infusion. The results are tabulated in Table 36. The maximum dexmedetomidine concentrations in schizophrenic patients (Cmax) ranged from about 22.45 pg/mL to about 406.3 pg/mL. Time to reach C_(max) ranged from about 15 minutes to about 105 minutes. Mean infusion rate is 0.36 mcg/kg/hr with the maximum rate ranging from about 0.2 mcg/kg/hr to about 0.6 mcg/kg/hr (see FIGS. 18 to 20 ).

TABLE 36 depicts the plasma concentrations (pg/ml) of schizophrenia patients at different timepoints during the infusion of dexmedetomidine hydrochloride and normal saline Plasma level concentration (picogram/ml) Time 1 2 3 4 5 7 8 9 11 12 14 16 17 18 (Mins) T T T T P P P P T T T T T T 0 BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ 15 22.45 BLQ BLQ BLQ BLQ BLQ 41.01 BLQ BLQ 2.56 15.87 48.36 30 14.72 BLQ BLQ BLQ BLQ BLQ BLQ BLQ 62.91 44.87 52.66 15.59 BLQ 54.53 45 BLQ BLQ BLQ BLQ BLQ BLQ 124.07 50.51 46.53 41.17 39.93 60 BLQ BLQ BLQ BLQ BLQ 150.47 108.6 406.3 67.88 75 BLO BLQ BLQ BLQ BLQ 158.54 72.26 90 44.3 BLQ BLQ BLQ BLQ 237.83 105 BLQ BLQ BLQ BLQ 267.3 120 BLQ BLQ BLQ BLQ 135 BLQ BLQ BLQ BLQ 150 BLQ BLQ BLQ BLQ 165 BLQ BLQ BLQ BLQ 180 BLQ BLQ BLQ BLQ Total 19 75 60 149 180 180 180 179 68 103 64 66 36 30 duration of infusion (Mins) *BLQ- below limit of quantification T- Treatment; P- Placebo

Discussion: The administration of dexmedetomidine hydrochloride by the IV route produced a >=50% reduction in PEC score in a total of 7 of 10 subjects, with one subject (Patient 1) responding at a Cmax of 22 pg/mL. 5 of 10 subjects (Patients 1, 2, 3, 16 and 17) exhibited a 40% reduction in PEC score at a Cmax of =<72 pg/mL. The good response rates at these plasma exposure levels indicated that sublingual dexmedetomidine hydrochloride administration at similar or higher Cmax exposure levels achieved good anti-agitation effects. As demonstrated in Example 7 above, sublingual dexmedetomidine hydrochloride administered to healthy volunteers produced good plasma exposure levels at doses of 10, 20 and 40 micrograms, indicating that such doses were suitable for obtaining good anti-agitation effects (e.g., as measured by a reduction in PEC score) in agitated subjects, including subjects with schizophrenia, without also producing clinically meaningful detrimental effects on blood pressure and/or heart rate.

Example 6: A Phase III Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Determine Efficacy and Safety of Dexmedetomidine Sublingual Film in Agitation Associated with Schizophrenia

Objectives:

Primary Objective

To determine if a single dose of Dexmedetomidine sublingual film effectively reduced symptoms of acute agitation associated with schizophrenia, schizoaffective disorder or schizophreniform disorder assessed using the Positive and Negative Syndrome Scale—Excited Component (PEC) change from baseline as compared to placebo.

Key Secondary Objective:

To determine the earliest time where an effect on agitation was apparent as measured by the change from baseline in PEC total score in contrast with placebo.

Other Exploratory Objectives:

1. Overall clinical improvement after drug administration as measured by the Clinical Global Impression-Improvement Scale (CGI-I) score.

2. Agitation-Calmness Evaluation Scale (ACES) scores at 2, 4 and 8 hrs after dose administration.

3. Change from baseline in total PEC score over time measured from 10 min through 24 hrs after dosing.

4. PEC Responders and CGI-I Responders at 2 hours following dose of Dexmedetomidine sublingual film, compared with placebo:

-   -   a. PEC responders were defined as those who achieve at least a         40% reduction in PEC total score from baseline at or before 2         hours post-dose.     -   b. CGI-I responders were defined as subjects with a score of 1         or 2 on the CGI-I scale (the CGI-I non-responders were defined         as subjects with scores from 3 to 7 at 2 hours).

5. Time to rescue medication during the entire 24 hrs Post-treatment Evaluation Period for subjects who received Dexmedetomidine sublingual film compared to placebo.

6. Proportion of subjects per treatment group who received rescue medication by 4 hrs and within 24 hrs after dosing.

7. Duration of calming effect as described by the change from baseline in PEC total score, and ACES score at 2, 4 and 8 hrs after dosing.

8. Describe effect on overall psychotic symptoms and subscales (PANSS total, positive, negative, and general psychopathology subscales)

9. Determine the safety profile of Dexmedetomidine sublingual film as measured by vital signs and treatment-emergent adverse event reports and vital signs.

10. Describe the overall tolerability in terms of adverse event reports and local site (oral/sublingual) tolerability of oral film.

11. Descriptive pharmacokinetics of Dexmedetomidine sublingual film in the patient population.

12. Determine patient acceptability, taste and likability of study medication using likert scales to capture subject's acceptability, opinion on taste and questions regarding likability.

Study Design: This was a randomized, double-blind, placebo-controlled Phase III study assessing efficacy, safety and tolerability of dexmedetomidine sublingual film dosing in adult (18-75 years old) males and females with acute agitation associated with schizophrenia, schizoaffective disorder, or schizophreniform disorder. This in-clinic study randomized subjects 1:1:1 to receive Dexmedetomidine sublingual film (180 μg or 120 μg dose of DEX) or matching placebo film. The randomization was be stratified by age; age <65 and age ≥65.

Eligible subjects (acutely agitated subjects with schizophrenia, schizoaffective, or schizophreniform disorder) might be identified in outpatient clinics, mental health, psychiatric or medical emergency services including medical/psychiatric observation units, or as newly admitted to a hospital setting for acute agitation or already hospitalized for chronic underlying conditions. Subjects were domiciled in a clinical research setting or hospitalized to remain under medical supervision while undergoing screening procedures to assess eligibility.

Upon confirmation of eligibility, subjects were randomized to receive either 180 μg or 120 μg Dexmedetomidine sublingual film or matching placebo. At the time of dosing, patients were instructed on how to take the investigational product sublingually, and that they should retain the investigational product in the sublingual cavity until dissolved. The patient was self-administered under the supervision of a trained staff member. If the patient was unable to self-administer, the event was recorded, and the subject's participation was concluded. In the event of persistent or recurrent agitation, investigators might chose to repeat dose at 90 μg or 60 μg (half of 180 μg or 120 μg film) after the 2-hour time point as measured by a PEC change from baseline <40% but in the absence of safety concerns. Patients could only be re-dosed if they were hemodynamically stable, not hypotensive (must be greater than 90/60 diastolic/systolic) and not bradycardic (must be greater than 60 bpm). Patients also could not be re-dosed if they were orthostatic (a drop of 20 points in either SBP or DBP) or if they were experiencing an AE that when assessed by the PI precludes redosing. The maximum number of repeat doses per subject was 2, during the 12 hours post first dose. Doses might not be administered sooner than 2 hours after a previous dose. If the PEC change from baseline was >40% repeat dosing was not allowed.

Participants were also be evaluated for local irritation around the area where the film was placed. Efficacy and safety assessments were conducted periodically before and after dosing. All efforts should be made to have the patient perform all assessments as per protocol. Vital Signs, pulse oximetry, and ECG with rhythm strip were measured as per schedule of assessments (Table 33), prior to any PK assessments. Participants were allowed water as desired 15 minutes after completion of dosing. Safety and tolerability assessments were conducted at various timepoints.

Any abnormal vital sign measurement, clinical laboratory test, physical examination finding, or ECG parameter deemed clinically significant by the investigator repeated, including test results obtained on the final study day or upon early termination. For any test abnormality deemed clinically significant, repeat analysis was performed during the follow-up period and until the value returns to baseline (or within normal limits) or the investigator deems the abnormality to be stable and no longer of clinical concern.

Approximately 4 mL of venous blood (to obtain a minimum of 1.2 mL plasma) was taken into K2-EDTA tubes at set time intervals for the determination of plasma concentrations of study drug (or Placebo). The PK plasma samples were collected within 10 min of the scheduled sampling time on Day 1.

Number of subjects (planned): Approximately 375 subjects were enrolled at up to 30 study sites in the United States.

Diagnosis and Main Criteria for Eligibility:

Inclusion Criteria:

-   -   (1) Male and female patients between the ages of 18 to 75 years,         inclusive.     -   (2) Patients who had met DSM-5 criteria for schizophrenia,         schizoaffective, or schizophreniform disorder.     -   (3) Patients who were judged to be clinically agitated at         Baseline with a total score of ≥14 on the 5 items (poor impulse         control, tension, hostility, uncooperativeness, and excitement)         comprising the PANSS Excited Component (PEC).     -   (4) Patients who had a score of ≥4 on at least 1 of the 5 items         on the PEC or PEC score at baseline     -   (5) Patients who read, understood and provided written informed         consent.     -   (6) Patients who were in good general health prior to study         participation as determined by a detailed medical history,         physical examination, 12-lead ECG with rhythm strip, blood         chemistry profile, hematology, urinalysis and in the opinion of         the Principal Investigator.     -   (7) Female participants, if of child-bearing potential and         sexually active, and male participants, if sexually active with         a partner of child-bearing potential, who agreed to use a         medically acceptable and effective birth control method         throughout the study and for one week following the end of the         study. Medically acceptable methods of contraception that might         be used by the participant and/or his/her partner included         abstinence, birth control pills or patches, diaphragm with         spermicide, intrauterine device (IUD), condom with foam or         spermicide, vaginal spermicidal suppository, surgical         sterilization and progestin implant or injection. Prohibited         methods included: the rhythm method, withdrawal, condoms alone,         or diaphragm alone.

Exclusion Criteria:

-   -   (1) Patients with agitation caused by acute intoxication,         including positive identification of alcohol by breathalyzer or         drugs of abuse (with the exception of THC) during urine         screening.     -   (2) Patients treated within 4 hours prior to study drug         administration with benzodiazepines, other hypnotics or oral or         short-acting intramuscular antipsychotics.     -   (3) Treatment with alpha-1 noradrenergic blockers (terazosin,         doxazosin, tamsulosin, alfuzosin, or prazocin) or other         prohibited medications.     -   (4) Patients with significant risk of suicide or homicide per         the investigator's assessment, or any patient with an answer of         “yes” to item 4 or 5 on the CSSRS.     -   (5) Female patients who had a positive pregnancy test at         screening or are breastfeeding.     -   (6) Patients who had hydrocephalus, seizure disorder, or history         of significant head trauma, stroke, transient ischemic attack,         subarachnoid bleeding, brain tumor, encephalopathy, meningitis,         Parkinson's disease or focal neurological findings.     -   (7) History of syncope or other syncopal attacks, current         evidence of hypovolemia, orthostatic hypotension (average of 1,         3 and 5 min measurements), a screening and baseline heart rate         of <55 beats per minutes or systolic blood pressure <110 mmHg or         diastolic BP <70 mmHg.     -   (8) Patients with laboratory or ECG abnormalities considered         clinically significant by the investigator or qualified designee         [Advanced heart block (second-degree or above atrioventricular         block without pacemaker), diagnosis of Sick sinus syndrome] that         would had clinical implications for the patient's participation         in the study.     -   (9) Patients with serious or unstable medical illnesses. These         include current hepatic (moderate severe hepatic impairment),         renal, gastroenterologic, respiratory, cardiovascular (including         ischemic heart disease, congestive heart failure),         endocrinologic, or hematologic disease.     -   (10) Patients who had received an investigational drug within 30         days prior to the current agitation episode.     -   (11) Patients who were considered by the investigator, for any         reason, to be an unsuitable candidate for receiving         dexmedetomidine; e.g., patients with a history of allergic         reactions to dexmedetomidine.

Study Treatments

Test Product, Dose, and Mode of Administration:

Dexmedetomidine hydrochloride was a thin film formulation of DEX for sublingual (SL) administration. Dosing delivers 180 μg or 120 μg of DEX sublingually. The product is a small, solid-dose film formulation, approximately 193.6 mm2 in area and 0.7 mm thick, designed to completely dissolve in the SL space within 1-3 minutes.

Reference Therapy, Dosage and Mode of Administration:

Matching placebo films was taken sublingually as described above.

Duration of Treatment: 1 day

Study Procedures

Subjects provided written informed consent before any study-related procedures were initiated, including the cessation of prohibited concomitant therapy.

The schedule of events performed during the study were provided in Table 37.

Treatment Evaluation Day 1 Pre- Day 2 Day Dose¹ Follow- 7 −1 hr Up (+1) (+2) Screening to Post Dose Time¹ 24 hr End Activity Pre- time 10 20 30 45 1 1.5 2 4 6 8 (−9/+12 Day 3 of Time point treatment 0 min min min min hr hr hr hr hr hr hr) Discharge Study Informed Consent X Medical History × Demographics X Weight X X Height X BMI X Alcohol X breathalyzer MINI X Physical Exam X X Safety Labs² X X X ECG with rhythm X X X X strip³ Pulse oximetry X X X X X X Resting vital signs⁴ X X X X X X X X X X X Orthostatic vital X X X X X X X X signs⁴ Admit to Unit X Inclusion/Exclusion X X criteria Randomization X Study drug X administration¹⁰ PANSS⁹ X X X PCRS⁵ X X X X PEC⁵ X X X X X X X X X X X X X ACESS X X X X CGI-Severity⁶ X X CGI-Improvement⁶ X X X X C-SSRS X X Buccal (SL) X X X X assessment for local irritation⁷ Likert scales X Likability Question X PK Sampling⁸ X X X Concomitant X X X X X X Medications Adverse Events X X X X X X Notes to the Schedule of Events: ¹Pre-dose assessments had a window of 60 minutes prior to dose with the exception of PEC and ACES which were performed within 15 minutes of dosing (15 to 0 min). All post-dose assessments had a window of −5/+15 minutes through the 1.5 hour assessments, −5/+25 minutes for the 2 hour assessments (with the exception of the PEC which will have a +/−5 minute window) and + 30 minutes for the 4, 6 and 8 hour assessments. ²Safety Labs were chemistry, hematology, urinalysis, UDS (local lab, only conducted at screening), alcohol breathalyzer (only conducted at screening), and urine pregnancy (only conducted at screening). Screening/enrollment labs: local labs drawn within 7 days prior to screening might suffice with the exception of urine drug screen. If results not available on the same day, a ‘desktop' or non-CLIA test might be performed; to confirm, results from a CLIA-certified laboratory was recorded once available. Central Labs was performed on Screening, Day 3 and Day 7. ³ECG for pre-dose did not need to be repeated if screening ECG was conducted on the day of dosing. ECGs collected following treatment were to be performed prior to PK assessments. ⁴Resting (recumbent) vital signs (SBP, DBP and HR) were taken upon having the subject recumbent for 5 min at Screening, Pre-dose and at 30 min, 1, 2, 4, 6, 8 and 24 hours post dose, as well as Day 3 and Day 7. Triplicate measurements performed in case of Systolic BP <90 mmHg, Diastolic BP <60 mmHg or Pulse <60 bpm. Orthostatic measurements (SBP, DBP, HR, respiratory rate and temperature) was taken upon having the subject stand, with measurements taken after 1, 3 and 5 minutes at Screening, Pre-dose, 2, 4, 8 and 24 hours post first dose, as well as Day 3 and Day 7. 5PEC was performed at Screening, Pre-dose (within 15 min prior to dose) and at 10, 20, 30, 45 min; 1, 1.5, 2, 4, 6, 8 and 24 hours post dose. The PCRS must be performed prior to PEC rating, when required. At 6 and 24 hrs the PEC rating must be performed before the PANSS interview. ACES was performed at Pre-dose (within 15 min of dose), 2, 4 and 8 hrs post dose. ⁶CGI-Severity was performed at Screening and pre-dose. CGI-Improvement was performed at 30 minutes, 1, 2 and 4 hours post dose. ⁷Buccal exam at 30 min, 2, 4 and 24 hr post-dose for local irritation. ⁸PK blood samples were collected 1, 4, and 8 hr (while awake) after dose. A sample might not be collected if the Physician indicated in source documents that the patient was in a mental state that was not conducive to PK sample collection. Non-compliance or refusal of all or any PK draw was not exclusionary nor result in ET. Vital signs were to be done prior to PK sample draws, when performed at the same timepoints. ⁹Pre-dose PANSS might be administered at any time prior to dosing on the day of dosing and 6 and 24 hrs (−1/+2 hr) post-dose. At 6 and 24 hrs PANSS interview must be performed after PEC rating. The 6 hour and 24 hr PANSS was conducted with reference to the predose PANSS. ¹⁰The investigator might choose to re-dose the patient with half of a film after the 2 hour post-dose assessments are performed if the PEC change from baseline is <40%. Patients could be re-dosed up to 2 times during 12 hours post first dose. All assessments listed in this Schedule of Events at the 2 hour post first dose timepoint repeated at 2 hours post every re-dose.

Criteria for Evaluation:

Efficacy assessment: Assessment of Drug Effects on acute agitation was done by the Positive and Negative Syndrome Scale—Excited Component (PEC). The PEC comprises 5 items associated with agitation: poor impulse control, tension, hostility, uncooperativeness, and excitement; each scored 1 (minimum) to 7 (maximum). The PEC, the sum of these 5 subscales, thus ranges from 5 to 35.

Overall agitation and sedation were evaluated with the Agitation-Calmness Evaluation Scale (ACES), where 1 indicates marked agitation; 2—moderate agitation; 3—mild agitation; 4—normal behavior; 5—mild calmness; 6—moderate calmness; 7—marked calmness; 8—deep sleep; and 9—unarousable.

The overall clinical improvement in agitation in response to treatment was also be measured by the Clinical Global Impressions-Improvement (CGI-I). CGI-I scores range from 1 to 7: 0=not assessed (missing), 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse.

Safety and tolerability assessments: AEs, clinical laboratory tests, ECG with rhythm strip, pulse oximetry, and vital signs were monitored for tolerability assessment. All observed and volunteered AEs were recorded. The relationship of AEs to the study drug were graded as not related, unlikely/remotely related, possibly related, probably related or definitely related by the investigators. Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate were monitored. The application site of the SL preparation (buccal mucosa) was inspected for any signs of local irritation

Additional Assessments:

Demographics, Medical and Psychiatric History, psychotic symptoms (PANSS), Smoking history, Prior and Concomitant Medication, Physical Examination, Pregnancy

Pharmacokinetics: A sparse PK sampling of plasma concentrations at specified timepoints were reported. A population PK/PD analysis of plasma concentration vs. clinical response was reported using a separate SAP and report. A graphical assessment of PK vs. vital signs and other potential PD parameters were included.

Statistical Analysis:

Efficacy Analyses

The primary efficacy endpoint of the study was the absolute change from baseline in the PEC total score at 120 min. The intent to treat population was analyzed and consist of all patients who took any study medication and who had both baseline and at least 1 efficacy assessment after dosing. The key secondary endpoints were: change from baseline in the PEC score at 90 min, 60 min, 45 min, 30 min, 20 min and 10 min. Other exploratory endpoints were same as listed under exploratory objectives.

Safety Analyses: Safety data analysis was conducted on all subjects receiving at least 1 dose of study drug. The number and percentage of subjects experiencing 1 or more AEs were summarized by treatment, relationship to study drug, and severity. AEs were coded using the Medical Dictionary for Regulatory Activities (Med DRA) terminology. Listings of subjects who experienced withdrawal due to an AE, serious AEs and/or death will be presented. Laboratory parameters were summarized by treatment using descriptive statistics and data listings of clinically significant abnormalities. Vital signs and ECG data were summarized by changes from baseline values using descriptive statistics.

Pharmacokinetic Analyses

Plasma concentrations and concentration-time data for dexmedetomidine were used to calculate PK parameters; these data and results were reported separately. All pharmacokinetic parameters were calculated using non-compartmental analysis using WinNonlin Version 5.2 or higher. Actual sampling times were used in all pharmacokinetic analyses. Per protocol times were used to calculate mean plasma concentrations for graphical displays. Other PK analyses were performed as appropriate.

Results Summary:

Demographics

The demographics and baseline characteristics is shown below in Table 38.

TABLE 38 Demographics Dexmedetomidine Sublingual film 180 ug 120 ug Placebo Overall (N = 126) (N = 129) (N = 126) (N = 381) Mean age 46.0 45.7 45.1 45.6 (years) (11.91) (11.32) (11.13) (11.43) Female N (%) 44 52 44 140 (34.9) (40.3) (34.9) (36.7) Race (% white/ 16.7/83.3 25.6/74.4 16.7/83.3 19.7/80.3 % non-white) BMI 32.53 31.24 32.56 32.10 (7.8) (7.6) (7.4) (7.6) Diagnosis 85.70% 87.60% 80.20% 84.50% Schizophrenia Schizophrenia 14.30% 12.40% 19.80% 15.50% Baseline PEC 17.6 17.5 17.6 NA means

Efficacy

Dexmedetomidine sublingual film significantly improved the severity of agitation from baseline as measured by PEC, ACES scales and CGI-I scores. Key efficacy findings at 2 hours post-dose are presented below.

(a) Primary Efficacy Endpoint (PEC reduction): a reduction in the PEC score (PANSS or the Positive and Negative Syndrome Scale, Excitatory Component) for agitation was observed with rapid calming without excessive sedation at the clinical regulatory endpoint and at earlier time-points. The primary efficacy endpoint was the mean change from baseline in PEC total score at 2 hours (120 minutes) compared to placebo. There were 2 dose cohorts (120 μg (N=129) and 180 μg (N=126)) and 126 placebo patients. Active patients in each of the 2 dose cohorts were compared to placebo patients. The change from baseline in PEC at 2 hours for patients treated with dexmedetomidine sublingual film was compared with placebo using a mixed model repeated measures (MMRM) analysis, with baseline PEC, treatment group, time, the interaction between treatment groups and time, and the interaction between baseline PEC and time as covariates.

The efficacy of dexmedetomidine hydrochloride sublingual film as measured by PEC reduction is dose-responsive and robust. The decrease from baseline in PEC score in the 180 μg dose group showed significant response with a −10.3 mean change from baseline (CFB) total PEC score at 2 hours post dosing compared to placebo (Table 39 and FIGS. 21A and 21B). Mean changes from baseline were −8.5 points for the 120 μg treatment groups, compared to placebo (−4.8 Mean change). Additionally, as early onset of action is an important attribute for therapy in reducing agitation, the 180 μg group showed a statistically significant separation from placebo as early as 20 minutes post dosing (FIG. 21A and FIG. 21B). Further, the decrease from baseline in PEC score in the 180 μg and 120 μg dose groups showed significant responses at 6 hours post dosing compared to placebo (FIG. 21B).

PEC Responder Analyses: The proportion of treatment responders, defined as those with a 40% decrease from baseline in PEC total score at 2 hours post dose, was greatest in the 180 μg group (87% for 180 μg, 67% for 120 μg) as compared to placebo (34%) (Table 39). The durability of calming effects of the 180 μg dose was remarkably prolonged with a sustained statistically significant reduction in PEC evident after 24 hrs.

TABLE 39 Summary of Change from Baseline at 2 hours in PANSS-PEC Total Score and Percent of Responders at 2 hours in the PEC Score by Treatment Group Dexmedetomidine Sublingual film Endpoint (120 min) 120 μg 180 μg PEC Total score N Placebo (N = 126) (N = 126) Change from N = 126 −4.8 −8.5 *** −10.3 *** Baseline (LSM) (180 μg) N = 129 (120 μg) Response ° 126 34% 67% 87% ° Proportion achieving ≥ 40% PEC reduction; * p < 0.025; *** p < 0.0001

Secondary Efficacy Endpoints:

Changes in secondary efficacy measures (i.e., ACES and CGI-I scores) at 2 hours post-dose were consistent with the results for PEC total scores and were indicative of improvement in symptoms of agitation after treatment with dexmedetomidine sublingual film.

ACES scores: A secondary objective for this study was to evaluate the duration of calming effect of dexmedetomidine sublingual thin film drug utilizing the Agitation-Calmness Evaluation Scale (ACES) collected at pre-dose, 2 hr, and 4 hr after first dose. The ACES assessment was consistent with the analysis of the primary endpoint, and met statistically significance for calming as measured by ACES at two hours compared to placebo in 120 μg and 180 μg (120 μg; p=0.0001) and (180 μg; p<0.0001). At 2 hours after dosing, subjects in the 120 μg and 180 μg treatment groups showed significantly greater improvements relative to placebo in ACES scores (+about 2.8 [P<0.0001] for 120 μg; +about 3.75 [P<0.0001] for 180 μg, compared to placebo of +about 1.0). The improvements at 4 hours post-dose were similar (+about 2.8 [P<0.0001] for 120 μg; +about 3.2 [P<0.0001] for 180 μg, compared to placebo of +about 1.0). (FIG. 22 ).

CGI-scores: The percentage of subjects achieving CGI-I scores of 1 or 2 (‘very much improved’ or ‘much improved’) at 2 hours post-dose was significantly higher in the 120 μg group (about 65% [p<0.0001]) and in the 180 μg dose group (about 90% [p<0.0001]), compared with placebo (about 35%). Significant improvements were also observed at 30 minutes, 1 hour, and 4 hours after dosing for both treatment groups [in the 180 μg dose group (p<0.0001) and in the 120 dose group (p<0.0075)] (FIG. 23 ).

Conclusion: Dexmedetomidine sublingual film treatment significantly improved the severity of agitation from baseline as measured by PEC, CGI-I, and ACES scales in schizophrenia patients. The primary efficacy endpoint was met in 120 μg, and 180 μg treatment groups as there was significant improvements in PEC total scores from baseline at 2 hours post-dose with mean changes of −8.5 and −10.3 points, respectively, versus −4.8 for placebo. Reduction in agitation was observed as early as 20 minutes compared to placebo. Further, changes in secondary efficacy measures (ie, CGI-I and ACES scores) at 2 hours post-dose were consistent with the results for PEC total scores and were indicative of improvement in symptoms of agitation after treatment with Dexmedetomidine sublingual film.

Example 7: A Phase III Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to determine the Efficacy and Safety of dexmedetomidine hydrochloride sublingual film in Subjects with Agitation associated with bipolar disorder (Serenity II)

Objectives:

Primary Endpoint

The primary efficacy endpoint of the study was the absolute change from baseline in the PEC total score at 2 hours. The intent to treat population was analyzed and consists of all patients who took any study medication and who had both baseline and at least 1 efficacy assessment after dosing. Observations recorded after use of rescue medication were censored.

Key Secondary Endpoint Included:

The key secondary efficacy endpoint was the earliest time where an effect on agitation was apparent as measured by change from baseline PEC total score in contrast with placebo.

Exploratory Endpoints Included:

-   -   1. Overall clinical improvement after drug administration as         measured by the Clinical Global Impression-Improvement Scale         (CGI-I) score.     -   2. Agitation-Calmness Evaluation Scale (ACES) scores at 2, 4 and         8 hrs after dose administration.     -   3. Change from baseline in total PEC score over time measured         from 10 min through 24 hrs. after dosing.     -   4. PEC Responders and CGI-I Responders at 2 hours following dose         of dexmedetomidine hydrochloride, compared with placebo:         -   a. PEC responders were defined as those who achieved at             least a 40% reduction in PEC total score from baseline at or             before 2 hours post-dose.         -   b. CGI-I responders were defined as subjects with a score of             1 or 2 on the CGI-I scale (the CGI-I non-responders were             defined as subjects with scores from 3 to 7 at 2 hours).     -   5. Time to rescue medication during the entire 24 hrs         Post-treatment Evaluation Period for subjects receiving         dexmedetomidine hydrochloride compared to placebo.     -   6. Proportion of subjects per treatment group who received         rescue medication by 4 hrs and within 24 hrs after dosing.     -   7. Duration of calming effect as described by the change from         baseline in PEC total score, and ACES score at 2, 4 and 8 hrs.         after dosing.     -   8. Determined the safety profile of dexmedetomidine         hydrochloride as measured by vital signs and treatment-emergent         adverse event reports.     -   9. Described the overall tolerability in terms of adverse event         reports and local site (oral/sublingual) tolerability of oral         film.     -   10. Descriptive pharmacokinetics of dexmedetomidine         hydrochloride in the patient population.     -   11. Determined patient acceptability, taste and likability of         study medication using Likert scales to capture subject's         acceptability, opinion on taste and questions regarding         likability.     -   12. Characterized the patient population utilizing the Young         Mania Rating Scale (YMRS).

Study Design:

The study enrolled approximately 381 subjects randomized 1:1:1 to dose regimens of 180 μg, 120 μg dexmedetomidine hydrochloride, or placebo stratified by age <65 and age ≥65. The doses were selected based on the results of the prior Phase Ib clinical trial.

Male and female adults with acute agitation associated with bipolar I or II disorder were enrolled.

Eligible subjects (acutely agitated subjects with bipolar I or II disorder, generally hypomanic, manic or mixed episodes) can be identified in outpatient clinics, mental health, psychiatric or medical emergency services, including medical/psychiatric observation units, or as newly admitted to a hospital setting for acute agitation or already in hospital for chronic underlying conditions. Subjects were domiciled in a clinical research setting or hospitalized to remain under medical supervision while undergoing screening procedures to assessed eligibility.

Upon confirmation of eligibility, subjects were randomized to 180 μg dexmedetomidine hydrochloride sublingual film or 120 μg dexmedetomidine hydrochloride sublingual film or matching placebo. Efficacy and safety assessments were conducted periodically before and after dosing.

Vital signs, pulse oximetry and ECG with rhythm strip were measured as per schedule of assessments, prior to any PK assessments. Participants were allowed water as desired 15 minutes after completion of dosing. Safety and tolerability assessments were conducted at various timepoints. Please refer to the Table 40 for Schedule of events.

Any abnormal vital sign measurement, clinical laboratory test, physical examination finding, or ECG parameter deemed clinically significant by the investigator were repeated, including test results obtained on the final study day or upon early termination. For any test abnormality deemed clinically significant, repeat analysis performed during the follow-up period and until the value returns to baseline (or within normal limits) or the investigator deemed the abnormality to be stable and no longer of clinical concern.

Approximately 4 mL of venous blood (to obtain a minimum of 1.2 mL plasma) was taken into K2-EDTA tubes at set time intervals for the determination of plasma concentrations of study drug (or placebo). The PK plasma samples were collected within 10 min of the scheduled sampling time on Day 1. Blood samples were collected per Table 40 Schedule of Events.

Discussion of Study Design

This was a definitive study to support the safety and efficacy evaluation of dexmedetomidine hydrochloride sublingual film for the acute treatment of agitation in bipolar disorder. The study was designed to characterize the efficacy, safety and tolerability of dexmedetomidine hydrochloride sublingual film in agitation associated with bipolar disorder. A dose of dexmedetomidine hydrochloride was chosen based on results that showed rapid efficacy in a large proportion of subjects was well tolerated and had an acceptable safety profile. In the event of persistent or recurrent agitation, investigators might chose to administer an additional reduced dose of 90 μg or 60 μg (half of 180 μg or 120 μg film) after the 2-hour time point as measured by a PEC change from baseline ≤40%, but in the absence of safety concerns. Patients could only be re-dosed if they were hemodynamically stable, not hypotensive (must be greater than 90/60 systolic/diastolic) and not bradycardic (must be greater than 60 bpm). Patients also could not be re-dosed if they were orthostatic (a drop of >20 mm Hg systolic, or 10 mm Hg diastolic) or if they were experiencing an Adverse Event (AE) that in the assessment of the PI precludes re-dosing. The maximum number of repeat doses per subject is 2, during the 12 hours post-first dose. Doses might not be administered sooner than 2 hours after a previous dose. If the PEC change from baseline is >40%, repeat dosing was not allowed.

Placebo was chosen as a comparator to more accurately assess efficacy as well as safety and tolerability. The randomized, double-blind parallel-group design ensures the sponsor, all subjects, and study staff involved were shielded from treatment assignment and outcomes and therefore minimized any potential bias. The randomization ratio provided an additional element that ensured blinding by decreasing the odds of guessing treatment arms.

Diagnosis and Main Criteria for Eligibility:

Inclusion Criteria

-   -   1. Male and female patients between the ages of 18 to 75 years,         inclusive.     -   2. Patients who had met DSM-5 criteria for bipolar I or II         disorder, generally hypomanic, manic or mixed episodes.     -   3. Patients who were judged to be clinically agitated at         Screening and Baseline with a total score of ≥14 on the 5 items         (poor impulse control, tension, hostility, uncooperativeness,         and excitement) comprising the PANSS Excited Component (PEC).     -   4. Patients who had a score of ≥4 on at least 1 of the 5 items         on the PEC at Baseline.     -   5. Patients who read, understand and provided written informed         consent.     -   6. Patients who were in good general health prior to study         participation as determined by a detailed medical history,         physical examination, 12-lead ECG with rhythm strip, blood         chemistry profile, hematology, urinalysis, and in the opinion of         the Principal Investigator.     -   7. Female participants, if of child-bearing potential and         sexually active, and male participants, if sexually active with         a partner of child-bearing potential, who agreed to use a         medically acceptable and effective birth control method         throughout the study and for one week following the end of the         study. Medically acceptable methods of contraception that might         be used by the participant and/or his/her partner include         abstinence, birth control pills or patches, diaphragm with         spermicide, intrauterine device (IUD), condom with foam or         spermicide, vaginal spermicidal suppository, surgical         sterilization, and progestin implant or injection. Prohibited         methods include: the rhythm method, withdrawal, condoms alone,         or diaphragm alone.

Exclusion Criteria

-   -   1. Patients with agitation caused by acute intoxication,         including positive identification of alcohol by breathalyzer or         drugs of abuse (with the exception of THC) during urine         screening.     -   2. Use of benzodiazepines or other hypnotics or antipsychotic         drugs in the 4 hours before study treatment.     -   3. Treatment with alpha-1 noradrenergic blockers (terazosin,         doxazosin, tamsulosin, alfuzosin, or prazosin) or other         prohibited medications.     -   4. Patients judged to be at serious risk of suicide must be         excluded.     -   5. Female patients who had a positive pregnancy test at         screening or are breastfeeding.     -   6. Patients who had hydrocephalus, seizure disorder, or history         of significant head trauma, stroke, transient ischemic attack,         subarachnoid bleeding, brain tumor, encephalopathy, meningitis,         Parkinson's disease or focal neurological findings.     -   7. History of syncope or other syncopal attacks, current         evidence of hypovolemia, orthostatic hypotension (average of 1,         3 and 5 min measurements), a screening and baseline heart rate         of <55 beats per minutes or systolic blood pressure <110 mmHg or         diastolic BP <70 mmHg.     -   8. Patients with laboratory or ECG abnormalities considered         clinically significant by the investigator or qualified designee         [Advanced heart block (second-degree or above atrioventricular         block without pacemaker), diagnosis of Sick sinus syndrome] that         would had clinical implications for the patient's participation         in the study.     -   9. Patients with serious or unstable medical illnesses. These         include current hepatic (moderate-severe hepatic impairment),         renal, gastroenterologic, respiratory, cardiovascular (including         ischemic heart disease, congestive heart failure),         endocrinologic, or hematologic disease.     -   10. Patients who had received an investigational drug within 30         days prior to the current agitation episode.     -   11. Patients who were considered by the investigator, for any         reason, to be an unsuitable candidate for receiving         dexmedetomidine hydrochloride, e.g., patients with a history of         allergic reactions to dexmedetomidine hydrochloride.

Study Treatments

Method of Assigning Subjects to Treatment Groups

Upon confirmation of eligibility, subjects were randomized to 180 μg dexmedetomidine hydrochloride film or 120 μg dexmedetomidine hydrochloride film or placebo. Randomization was 1:1:1 (180 μg or 120 μg dexmedetomidine hydrochloride or placebo and stratified by age <65, age ≥65) with 125 patients assigned to each arm by a permuted block design. Study randomization was computer generated.

Test Product, Dose, and Mode of Administration:

Dexmedetomidine hydrochloride was in a film formulation for sublingual (SL) administration. Dosing delivered 180 μg or 120 μg of dexmedetomidine hydrochloride sublingually. The product was a small, solid-dose film formulation, approximately 193.6 mm2 in area and 0.7 mm thick, designed to completely dissolve in the SL space within about 1-3 minutes.

Treatment Administration

At the time of dosing, patients were instructed on how to take dexmedetomidine hydrochloride film sublingually, and that they should retained the dexmedetomidine hydrochloride film in the sublingual cavity until dissolved. The patient self-administered under the supervision of a trained staff member. If the patient was unable to self-administer, the event was recorded, and the subject's participation was concluded.

In the event of persistent or recurrent agitation, investigators might choose to re-dose at 90 μg or 60 μg (dividing the 180 μg or 120 μg film in half) after the 2-hour time point as measured by a PEC change from baseline ≤40% but in the absence of safety concerns.

Study Procedures

Subjects provided written informed consent before any study-related procedures were initiated, including the cessation of concomitant therapy.

The schedule of events performed during the study was provided in Table 40.

Day 2 Pre- Treatment Evaluation Day 1 Follow-Up Day 7 Screening Dose¹ Post Dose Time¹ +1 (+2) Activity Pre- −1 hr to 10 20 30 45 1 1.5 2 4 6 8 24 hr Day 3 End of Time point treatment time 0 min min min min hr hr hr hr hr hr (−9/+12 hr) Discharge Study Informed Consent X Medical History X Demographics X Weight X X Height X BMI X Alcohol Breathalyzer X MINI X Physical Exam X X Safety Labs² X X X ECG with rhythm strip³ X X X X Pulse oximetry X X X X X X Resting vital signs⁴ X X X X X X X X X X X Orthostatic vital signs⁴ X X X X X X X X Admit to Unit X Inclusion/Exclusion X X criteria Randomization X Study drug X administration⁹ YMRS X X PCRS⁵ X X X X PEC⁵ X X X X X X X X X X X X X ACES⁵ X X X X CGI-Severity⁶ X X CGI-Improvement⁶ X X X X C-SSRS X X X X Buccal (SL) assessment X X X X for local irritation⁷ Likert Scales X Likability Questions X Pharmacokinetic X X X Sampling⁸ Concomitant Meds X X X X X Adverse Events X X X X X X Notes to the Schedule of Events: ¹Pre-dose assessments had a window of 60 minutes prior to dose with the exception of PEC and ACES which were performed within 15 minutes of dosing (15 to 0 min). All post-dose assessments had a window of −5/+15 minutes through the 1.5 hour assessments, −5/+25 minutes for the 2 hour assessments (with the exception of the PEC which had a +/−5 minute window) and ± 30 minutes for the 4, 6 and 8 hour assessments and YMRS could be performed at any time. ²Safety Labs included chemistry, hematology, urinalysis, UDS (local lab, only conducted at screening), alcohol breathalyzer (only conducted at screening,), and urine pregnancy (only conducted at screening) Screening/enrollment labs: local labs drawn within 7 days prior to screening might suffice with the exception of urine drug screen. If results not available on the same day, a ‘desktop' or non-CLIA test might be performed; to confirm, results from a CLIA-certified laboratory should be recorded once available. Central Labs should be performed on Screening, Day 3 and Day 7. ³ECG for pre-dose does not need to be repeated if screening ECG was conducted on the day of dosing. ECGs collected following treatment were performed prior to PK assessments. ⁴Resting (recumbent) vital signs (SBP, DBP, and HR) were taken upon having the subject recumbent for 5 min at Screening. Pre-dose and at 30 min, 1, 2, 4, 6, 8 and 24 hours post dose, as well as Day 3 and Day 7. Triplicate measurements were performed in case of Systolic BP <90 mmHg, Diastolic BP <60 mmHg or Pulse <60 bpm. Orthostatic measurements (SBP, DBP, HR, respiratory rate) were taken upon having the subject stand, with measurements taken after 1, 3 and 5 minutes and temperature were taken at Screening, Pre-dose, 2, 4, 8 and 24 hours post first dose as well as Day 3 and Day 7. ⁵PEC was performed at Screening, Pre-dose (within 15 min prior to dose) and at 10, 20, 30, 45 min; 1, 1.5, 2, 4, 6, 8 and 24 hours post dose. The PCRS must be performed prior to PEC rating, when required. ACES was performed at Pre-dose (within 15 min of dose), 2, 4, and 8 hrs post dose. ⁶CGI-Severity was performed at Screening and pre-dose. CGI-Improvement was performed at 30 minutes, 1, 2, and 4 hours post dose. ⁷Buccal examined at 30 min, 2, 4 and 24 hr post-dose for local irritation. ⁸PK blood samples were collected 1, 4, and 8 hr (while awake) after dose. A sample might not be collected if the Physician indicated in source documents that the patient was in a mental state that was not conducive to PK sample collection. Non-compliance or refusal of all or any PK draw was not exclusionary nor result in ET. Vital signs were to be done prior to PK sample draws, when performed at the same timepoints. ⁹The investigator might chose to re-dose the patient after the 2 hour post-dose assessments are performed if the PEC change from baseline is ≤40%. Patients could re-dosed after completing the 2 hour post first dose assessments. Repeat dosing administers half of a film. Patients could redosed twice in the 12 hour period post first dose. All assessments listed in this Schedule of Events at the 2 hour post first dose timepoint should be repeated at 2 hours post every re-dose. Assessments at 4, 6, or 8 hour post first dose that occur within 1 hour of a post re-dose assessment were not required to be performed

Study Assessments

Efficacy

The effect of study drug was evaluated using several validated instruments as described below.

PANSS—Excitatory Component (PEC)

Agitation-Calmness Evaluation Scale (ACES)

CGI-S and CGI-I

Clinical Global Impression of Severity (CGI-S) was rated based upon the severity of agitation at screening and pre-dose (immediately prior to start of dosing).

Severity of illness was assessed based on following scale:

-   -   0=Not assessed     -   1=Not at all ill     -   2=Borderline mentally ill     -   3=Mildly ill     -   4=Moderately ill     -   5=Markedly ill     -   6=Severely ill     -   7=Among the most extremely ill subjects

Drug response on agitation was evaluated by the Clinical Global Impressions-Improvement (CGI-I). It was performed at 30 minutes, 1, 2 and 4 hrs post dose. The CGI-I scores range from 1 to 7:

-   -   0=not assessed (missing),     -   1=very much improved,     -   2=much improved,     -   3=minimally improved,     -   4=no change,     -   5=minimally worse,     -   6=much worse,     -   7=very much worse

Both CGI-I and CGI-S were focused on the severity of agitation rather than the severity of the overall illness of bipolar disorder.

Young Mania Rating Scale (YMRS)

The YMRS was an 11-item scale evaluating mania symptoms based on the patient's subjective report of their clinical condition. It was used to characterize the patient population enrolled in the study.

Placebo-Control Reminder Script (PCRS)

The Placebo-Control Reminder Script (PCRS) © Hassman and Cohen, 2019, Version 5.0 educates clinical trial participants of key causes of the placebo and nocebo effects, namely the tempering of participant study expectations, reminding subjects what a placebo is and how that relates to their reporting of symptoms and potential side effects, and explaining how interactions with research site staff differ from their experience with previous providers. To do this, the PCRS informs subjects that they were to be honest about their symptoms, site staff had no expectations of symptom improvement or worsening and was not disappointed if they feel better, worse or the same, and asked participants to explain in their own words its content to ensure comprehension. The PEC Rater was read the PCRS study source before administering the PEC to each subject at each visit (time point) listed on the study specific PCRS, typically taking about 2 minutes to read.

Likert Scales

After dosing with the study drug, subjects assessed their preference of the study medication by answering the statements “I like the taste of the medication” and “The medication is acceptable” using a five-level Likert scale as below:

-   -   Strongly disagree     -   Disagree     -   Neither agree nor disagree     -   Agree     -   Strongly agree

Drug Likability

Subjects responded to open ended questions regarding their experience. Additional comments about aftertaste, smell, dissolve time, etc. were asked as Yes/No questions with Yes responses prompting an explanation field.

Safety

Safety was assessed during the study by the monitoring and recording of AEs, clinical laboratory test results (hematology, biochemistry, and urinalysis), vital sign measurements (systolic and diastolic blood pressures, heart rate measured as pulse, respiratory rate, and temperature), ECG, and physical examination findings. Should a known safety issue be identified (e.g., a high incidence of severe hypotension or bradycardia in the active 180 μg dose arm or the 120 μg arm), the DSMB notified the sponsor. Should this occur, sponsor notified FDA, and sponsor might chose to continue dosing the patients at a lower dose.

Pharmacokinetics

Blood samples (4 ml) were collected per Table 40—Schedule of Events. For each subject, up to 3 blood samples (12 mL of blood) were collected during the study for PK analysis. In addition, approximately 30 mL of blood was collected at screening, approximately 15 mL of blood was collected at Day 3 Discharge, and approximately 15 mL of blood was collected at Day 7(+2) for clinical laboratory testing. The total volume of blood collected during the study was expected to be approximately 72 mL. For each subject, up to 3 blood samples (12 mL of blood) were collected during the study for PK analysis. In addition, approximately 30 mL of blood was collected at screening, approximately 15 mL of blood was collected at Day 3 Discharge, and approximately 15 mL of blood was collected at Day 7(+2) for clinical laboratory testing. The total volume of blood collected during the study was expected to be approximately 72 mL.

Statistical Analyses

Pharmacokinetic Analyses

Plasma concentrations and concentration-time data for dexmedetomidine were used to calculate PK parameters; these data and results were reported separately. Details regarding the analyses of PK data were described in a separate PK SAP. The separate SAP for the PK analyses was prepared and finalized prior to database lock.

Safety Analyses

All safety analyses were performed using the Safety Population. All subjects who received at least one dose of study drug were included in the population for safety analysis. Adverse events (AEs) were characterized by type, severity, seriousness, and relationship to treatment. Adverse events were coded by preferred term and system organ class using MedDRA version 20.0.

Efficacy Analyses

The primary efficacy endpoint of the study was the absolute change from baseline in the PEC total score at 120 min. The intent to treat population was analyzed and consist of all patients who took any study medication and who had both baseline and at least 1 efficacy assessment after dosing.

Results Summary:

Demographics

The demographics and baseline characteristics is shown below in Table 41.

TABLE 41 Demographics Dexmedetomidine sublingual film 180 μg 120 μg Placebo Overall (N = 126) (N = 129) (N = 126) (N = 381) Mean age (years) 46.0 45.7 45.1 45.6 (11.91) (11.32) (11.13) (11.43) Female N (%) 44 52 44 140 (34.9) (40.3) (34.9) (36.7) Race (% white/ 38.9/61.1 44.4/55.6 39.7/60.3 41.0/59 % non-white) BMI 32.53 31.24 32.56 32.10 (7.8) (7.6) (7.4) (7.6) Diagnosis: Depressed 22% 16% 21% 20% Diagnosis: Hypomania  4% 11%  8%  8% Diagnosis: Mania 47% 46% 50% 47% Diagnosis: Mixed 24% 21% 17% 21% Episodes Diagnosis: Unspecified  3%  6%  4%  4% Baseline PEC means 18 18 17.9 NA

3. Efficacy

Dexmedetomidine sublingual film significantly improved the severity of agitation from baseline as measured by PEC, ACES scales and CGI-I scores. Key efficacy findings at 2 hours post-dose are presented below.

(a) Primary Efficacy Endpoint (PEC reduction): a reduction in the PEC score (PANSS or the Positive and Negative Syndrome Scale, Excitatory Component) for agitation was observed with rapid calming without excessive sedation at the clinical regulatory endpoint and at earlier time-points. The primary efficacy endpoint was the mean change from baseline in PEC total score at 2 hours (120 minutes) compared to placebo. There were 2 dose cohorts (120 μg (N=129) and 180 μg (N=126)) and 126 placebo patients. Active patients in each of the 2 dose cohorts were compared to placebo patients. The change from baseline in PEC at 2 hours for patients treated with dexmedetomidine sublingual film was compared with placebo using a mixed model repeated measures (MMRM) analysis, with baseline PEC, treatment group, time, the interaction between treatment groups and time, and the interaction between baseline PEC and time as covariates.

The efficacy of dexmedetomidine hydrochloride sublingual film as measured by PEC reduction is dose-responsive and robust. The decrease from baseline in PEC score in the 180 μg dose group showed significant response with a −10.4 mean change from baseline (CFB) total PEC score at 2 hours post dosing compared to placebo (Table 42 and FIG. 24A and FIG. 24 .B). Mean changes from baseline were −9.1 points for the 120 μg treatment groups, compared to placebo (−5 Mean change). Additionally, as early onset of action is an important attribute for therapy in reducing agitation, the 180 μg group showed a statistically significant separation from placebo as early as 20 minutes post dosing (FIG. 24A and FIG. 24 .B). Further, the decrease from baseline in PEC score in the 180 μg and 120 μg dose groups showed significant responses at 6 hours post dosing compared to placebo (FIG. 24B).

TABLE 42 Summary of Change from Baseline at 2 hours in PANSS-PEC Total Score and Percent of Responders at 2 hours in the PEC Score by Treatment Group Dexmedetomidine sublingual film Endpoint (120 min) N Placebo 120 μg 180 μg PEC Total score 126 −5.0 −9.1 *** −10.4 *** Change from (180 μg) Baseline (LSM) 129 (120 μg) Response ° 126 37% 69% 85% ° Proportion achieving ≥ 40% PEC reduction; * p < 0.025; *** p < 0.0001

PEC Responder Analyses: The proportion of treatment responders, defined as those with a 40% decrease from baseline in PEC total score at 2 hours post dose, was greatest in the 180 μg group (85% for 180 μg, 69% for 120 μg)) as compared to placebo (37%) (Table 42). The durability of calming effects of the 180 μg dose was remarkably prolonged with a sustained statistically significant reduction in PEC evident after 24 hrs.

Secondary Efficacy Endpoints:

Changes in secondary efficacy measures (i.e., ACES and CGI-I scores) at 2 hours post-dose were consistent with the results for PEC total scores and were indicative of improvement in symptoms of agitation after treatment with dexmedetomidine sublingual film.

ACES scores: A secondary objective for this study was to evaluate the duration of calming effect of dexmedetomidine sublingual thin film drug utilizing the Agitation-Calmness Evaluation Scale (ACES) collected at pre-dose, 2 hr, and 4 hr after first dose. The ACES assessment was consistent with the analysis of the primary endpoint, and met statistically significance for calming as measured by ACES at two hours compared to placebo in 120 μg and 180 μg (120 μg; p<0.0001) and (180 μg; p<0.0001). At 2 hours after dosing, subjects in the 120 μg and 180 μg treatment groups showed significantly greater improvements relative to placebo in ACES scores (+about 3.0 [p<0.0001] for 120 μg; +about 3.7 [p<0.0001] for 180 μg, compared to placebo of +about 1.0. The improvements at 4 hours post-dose were similar (+about 2.8 [p<0.0001] for 120 μg; +about 3.2 [p<0.0001] for 180 μg, compared to placebo of +about 1.0) (FIG. 25 ).

CGI scores: The percentage of subjects achieving CGI-I scores of 1 or 2 (‘very much improved’ or ‘much improved’) at 2 hours post-dose was significantly higher in the 120 μg group (about 70% [p<0.0001]) and in the 180 μg dose group (about 90% [p<0.0001]), compared with placebo (about 38%). Significant improvements were also observed at 30 minutes, 1 hour, and 4 hours after dosing for both treatment groups (FIG. 26 ).

Safety and Tolerability:

Dexmedetomidine sublingual film (formulations of Example 2) was well tolerated in schizophrenia and bipolar I disorder patients and had a favourable safety profile in the treatment of subjects with agitation. An overview of subjects who experienced at least 1 treatment emergent adverse event (TEAE) by treatment group for the safety population is given in Table 43.

TABLE 43 Summary of adverse events in Phase III trial (schizophrenia and bipolar disorder patient) Dexmedetomidine sublingual film 180 μg 120 μg Placebo Event (N = 252) (N = 255) (N = 252) Somnolence Mild 40 (15.9) 43 (16.9) 15 (6.0)  Moderate 16 (6.3)  11 (4.3)  1 (0.4) Dizziness Mild 13 (5.2)  7 (2.7) 2 (0.8) Moderate 2 (0.8) 3 (1.2) 0 Hypotension Mild 10 (4.0)  10 (3.9)  0 Moderate 3 (1.2) 4 (1.6) 0 Orthostatic Mild 9 (3.6) 7 (2.7) 1 (0.4) hypotension Moderate 4 (1.6) 0 0 Hypoaesthesia oral 12 (4.8)  7 (2.7) 1 (0.4) Dry mouth 11 (4.4)  19 (7.5)  3 (1.2) Nausea 7 (2.8) 6 (2.4) 4 (1.6) Headache 6 (2.4) 12 (4.7)  12 (4.8)  Paraesthesia oral 6 (2.4) 7 (2.7) 1 (0.4)

Conclusion: Dexmedetomidine sublingual film treatment significantly improved the severity of agitation from baseline as measured by PEC, CGI-I, and ACES scales in schizophrenia patients. The primary efficacy endpoint was met in 120 μg, and 180 μg treatment groups as there was significant improvements in PEC total scores from baseline at 2 hours post-dose with mean changes of −9.1 and −10.4 points, respectively, versus −5.0 for placebo. Reduction in agitation was observed as early as 20 minutes compared to placebo. Further, changes in secondary efficacy measures (i.e., CGI-I and ACES scores) at 2 hours post-dose were consistent with the results for PEC total scores and were indicative of improvement in symptoms of agitation after treatment with Dexmedetomidine sublingual film

Example 8: Exemplary Oromucosal Formulations

TABLE 44 Composition for a tablet formulation used for oromucosal delivery (with muco-adhesive properties) Ingredient(s) Amount % w/v Dexmedetomidine hydrochloride 180 μg  0.36% (equivalent to dexmedetomidine) Lactose Monohydrate 44.27 mg 88.54% Hypromellose (or) Hydroxy propyl 2.5 mg  5.0% cellulose (or) Polyethylene oxide (or) Xanthan gum (or) Sodium alginate Croscarmellose Sodium (or) 2.5 mg  5.0% sodium starch glycollate Sucralose 0.05 mg  0.1% Magnesium Stearate 0.5 mg  1.0% Tablet weight 50.0 mg   100%

Manufacturing Process:

-   -   1. Dexmedetomidine, binder (hypromellose (or) hydroxy propyl         cellulose (or) polyethylene oxide (or) xanthan gum (or) sodium         alginate) and sucralose are dissolved or dispersed in water to         prepare a solution or dispersion.     -   2. Remaining ingredients except magnesium stearate are blended         in a suitable mixer and sifted with the help of an appropriate         sieve.     -   3. The blend obtained in step 2 is granulated using a suitable         granulator.     -   4. Granules are dried in a suitable fluid bed dryer or any other         suitable dryer and size appropriately in quadro-co-mill or         multimill.     -   5. Granules are loaded into a suitable blender such as V-blender         and lubricate with magnesium stearate.     -   6. The lubricated blend obtained in step 5 is compressed into         tablets of specific dimensions using appropriate tooling.

TABLE 45 Composition for a tablet formulation used for buccal delivery (with muco-adhesive nature) Ingredient(s) Amount % w/v Dexmedetomidine hydrochloride 180 μg  0.36% (equivalent to dexmedetomidine) Lactose monohydrate 43.77 mg 87.54% Hypromellose (or) Hydroxy propyl 5.0 mg  10.0% cellulose (or) Polyethylene oxide (or) Xanthan gum (or) Sodium alginate Sucralose 0.05 mg  0.1% Magnesium Stearate 0.5 mg  1.0% Talc 0.5 mg  1.0% Tablet weight 50.0 mg   100%

Manufacturing Process:

-   -   1. Dexmedetomidine hydrochloride, binder (hypromellose (or)         hydroxy propyl cellulose (or) polyethylene oxide (or) xanthan         gum (or) sodium alginate) and sucralose are dissolved or         dispersed in water to prepare a solution or dispersion.     -   2. Remaining ingredients except magnesium stearate and talc are         blended in a suitable mixer and sifted with the help of an         appropriate sieve.     -   3. The blend obtained in step 2 is granulated using a suitable         granulator.     -   4. Granules are dried in a suitable fluid bed dryer or other         dryer and size appropriately in quadro-co-mill or multimill.     -   5. Granules are loaded into a suitable blender such as V-blender         and lubricated with magnesium stearate and talc.     -   6. The lubricated blend obtained in step 5 is compressed into         tablets of specific dimensions using appropriate tooling.

TABLE 46 Composition for Dexmedetomidine hydrochloride spray formulation for sublingual delivery Ingredients Amount % w/v Dexmedetomidine 180 μg   0.18% hydrochloride (equivalent to dexmedetomidine) N-Methylpyrrolidone (or) 10 μL   10% Propylene Glycol (or) Polyethylene glycol (or) Glycerine Ethanol 5 μL    5% Sucralose 0.1 mg    0.1% Peppermint Oil 1 μL    1.0% Purified water q.s. 100 μL q.s. 100%

Manufacturing Process:

-   -   1. The polymer (N-methylpyrrolidone (or) propylene glycol (or)         polyethylene glycol) or glycerine is dissolved or dispersed in a         part of the total water quantity.     -   2. Dexmedetomidine hydrochloride is mixed with rest of the         excipients and the solution or dispersion obtained in step 1.     -   3. The final volume is made with water in a suitable vessel.     -   4. The resultant solution is filled into appropriate spray         canisters using appropriate tooling such as metered nozzles.

TABLE 47 Composition for Dexmedetomidine hydrochloride drops formulation for sublingual delivery Ingredient(s) Amount % w/v Dexmedetomidine 180 μg   0.18% hydrochloride (equivalent to dexmedetomidine) Povidone or Hypromellose 5 mg    5.0% or Carbopol N-Methylpyrrolidone (or) 10 μL   10.0% propylene glycol (or) polyethylene glycol (or) glycerine (or) ethanol Sucralose 0.1 mg    0.1% Peppermint oil 1 μL    1.0% Purified water q.s. 100 μL q.s. 100%

Manufacturing Process: Simple Mixing Process

-   -   1. The polymer (N-methylpyrrolidone (or) propylene glycol (or)         polyethylene glycol) or Glycerine is dissolved or dispersed in a         part of the total water quantity.     -   2. Dexmedetomidine hydrochloride is mixed with rest of the         excipients and the solution or dispersion obtained in step 1.     -   3. The final volume is made with water in a suitable vessel.     -   4. The resultant solution is filled into appropriate pack or         bottles.

TABLE 48 Composition for Dexmedetomidine hydrochloride gel formulation for sublingual delivery Ingredient(s) Amount % w/v Dexmedetomidine 180 μg   0.18% Carbopol or 10 mg   10.0% Hypromellose or HPC or CMC N-Methylpyrrolidone 10 μL   10.0% (or) Propylene Glycol (or) Polyethylene glyol (or) Glycerine (or) Ethanol Sucralose 0.1 mg    0.1% Peppermint Oil 1 μL    1.0% Purified water q.s. 100 μL q.s. 100%

Manufacturing Process:

-   -   1. The polymer (N-methylpyrrolidone (or) propylene glycol (or)         polyethylene glycol) or glycerine) is dissolved or dispersed in         a part of the total water quantity.     -   2. Remaining ingredients are dissolved or dispersed in other         part of the water.     -   3. Resultant solutions or dispersions of Step 1 and step 2 are         mixed and final volume is made.     -   4. The resultant mixture of step 3 is packed into appropriate         pack or containers

Example 9. Some aspects of the disclosed invention are directed to two phase III Multicenter, Randomized, Double-blind, Placebo-controlled Studies to determine Efficacy and Safety of Dexmedetomidine sublingual film in agitation associated with schizophrenia and in bipolar disorder as reported in Examples 6 and 7 and in US approved label of IGALMI™ (dexmedetomidine) that is incorporated herein in its entirety.

The following is a draft of prescribing information or approved label in US:

IGALMI™ (dexmedetomidine) sublingual film, for sublingual or buccal use:

Indications and Usage

IGALMI™ is indicated for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults.

Limitations of Use:

The safety and effectiveness of IGALMI™ have not been established beyond 24 hours from the first dose.

Dosage and Administration

Important Recommendations Prior to Initiating IGALMI™ and During Therapy

IGALMI™ should be administered under the supervision of a healthcare provider. A healthcare provider should monitor vital signs and alertness after IGALMI™ administration to prevent falls and syncope

IGALMI™ is for sublingual or buccal administration. Do not chew or swallow IGALMI™. Do not eat or drink for at least 15 minutes after sublingual administration, or at least one hour after buccal administration.

Recommended Dosage

Table 49 includes dosage recommendations for IGALMI™ based on agitation severity for adults, patients with hepatic impairment, and geriatric patients. Lower dosages are recommended for patients with hepatic impairment and geriatric patients.

If agitation persists after the initial dose, up to two additional doses may be administered at least two hours apart. The dosage recommendations for additional doses vary depending upon the patient population and agitation severity (see Table 49). Assess vital signs including orthostatic measurements prior to the administration of any subsequent doses.

Due to risk of hypotension, additional half-doses are not recommended in patients with systolic blood pressure (SBP) less than 90 mmHg, diastolic blood pressure (DBP) less than 60 mmHg, heart rate (HR) less than 60 beats per minute, or postural decrease in SBP ≥20 mmHg or in DBP ≥10 mmHg.

TABLE 49 Dosage Recommendations for IGALMI ™ in Adults, Adult Patients with Hepatic Impairment, and Geriatric Patients with Agitation Associated with Schizophrenia or Bipolar I or II Disorder Maximum Optional Recommended Patient Agitation Initial 2^(nd)/3^(rd) Total Population Severity Dose* Doses* Daily Dosage Adults Mild or 120 mcg 60 mcg 240 mcg Moderate Severe 180 mcg 90 mcg 360 mcg Patients with Mild Mild or  90 mcg 60 mcg 210 mcg or Moderate Moderate Hepatic Impairment† Severe 120 mcg 60 mcg 240 mcg Patients with Mild or  60 mcg 60 mcg 180 mcg Severe Hepatic Moderate Impairment† Severe  90 mcg 60 mcg 210 mcg Geriatric Mild, 120 mcg 60 mcg 240 mcg Patients (≥65 Moderate, years old) or Severe *IGALMI ™ 120 mcg and 180 mcg dosage strengths may be cut in half to obtain the 60 mcg and 90 mcg doses, respectively †Hepatic impairment: Mild (Child-Pugh Class A); Moderate (Child-Pugh Class B); Severe (Child-Pugh Class C)

Preparation and Administration Instructions

Keep IGALMI™ in the foil pouch until ready to administer. IGALMI™ should be immediately administered once the pouch is opened and the dose prepared.

Prepare and administer IGALMI™ under the supervision of a healthcare provider as follows:

-   -   1. Open the sealed foil pouch by tearing straight across at the         notch.         -   (i) Perform Steps 2a, 2b, 2c and 2d only if a 60 mcg or 90             mcg dose (half of a film) is needed, then proceed to Step 3.         -   (ii) If administering a full dose (1 film), proceed directly             to Step 3.     -   2a. Remove the film from the pouch with clean dry hands.     -   2b. Cut the film in half between the dots with clean, dry         scissors.     -   2c. Discard unused half in waste container.     -   2d. Place the half film for administration to the patient back         into the pouch.     -   3. Immediately give the pouch to the patient.     -   4. Instruct patient to remove the film from the pouch with clean         dry hands.     -   5. For sublingual administration: Instruct patient to place film         under the tongue. The film will stick in place. Note: Patient         may not eat or drink for 15 minutes after sublingual         administration.     -   6. For buccal administration: Instruct patient to place film         behind lower lip. The film will stick in place. Note: Patient         may not eat or drink for one hour after buccal administration.     -   7. Instruct patient to:         -   (a) Close their mouth.         -   (b) Allow the film to dissolve.         -   (c) Do not chew or swallow the film.

Dosage Forms and Strengths

IGALMI™ is a blue rectangular sublingual film containing on its surface two darker blue spots in dose strengths of 120 mcg and 180 mcg.

CONTRAINDICATIONS: None.

Warnings and Precautions

Hypotension, Orthostatic Hypotension, and Bradycardia

IGALMI™ causes dose-dependent hypotension, orthostatic hypotension, and bradycardia. In clinical studies, 18%, 16%, and 9% of patients treated with 180 mcg of IGALMI™, 120 mcg of IGALMI™, and placebo, respectively, experienced orthostatic hypotension (defined as SBP decrease ≥20 mmHg or DBP decrease ≥10 mmHg after 1, 3, or 5 minutes of standing) at 2 hours post-dose. In those studies, 7%, 6%, and 1% of patients treated with 180 mcg of IGALMI, 120 mcg of IGALMI™, and placebo, respectively, experienced HR ≤50 beats per minute within 2 hours of dosing. In clinical studies with IGALMI™, patients were excluded if they had treatment with alpha-1 noradrenergic blockers, benzodiazepines, other hypnotics or antipsychotic drugs four hours prior to study drug administration; had a history of syncope or syncopal attacks; SBP <110 mmHg; DBP <70 mmHg; HR<55 beats per minute; or had evidence of hypovolemia or orthostatic hypotension.

Reports of hypotension and bradycardia, including some resulting in fatalities, have been associated with the use of another dexmedetomidine product given intravenously (IGALMI™ is for sublingual or buccal use and is not approved for intravenous use). Clinically significant episodes of bradycardia and sinus arrest have been reported after administration of this other dexmedetomidine product to young, healthy adult volunteers with high vagal tone and when this product was given by rapid intravenous or bolus administration.

Because IGALMI™ decreases sympathetic nervous system activity, hypotension and/or bradycardia may be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension, and in geriatric patients.

Avoid use of IGALMI™ in patients with hypotension, orthostatic hypotension, advanced heart block, severe ventricular dysfunction, or history of syncope. After IGALMI™ administration, patients should be adequately hydrated and should sit or lie down until vital signs are within normal range. If a patient is unable to remain seated or lying down, precautions should be taken to reduce the risk of falls. Ensure that a patient is alert and not experiencing orthostatic hypotension or symptomatic hypotension prior to allowing them to resume ambulation.

QT Interval Prolongation

IGALMI prolongs the QT interval. Avoid use of IGALMI™ in patients at risk of torsades de pointes or sudden death including those with known QT prolongation, a history of other arrhythmias, symptomatic bradycardia, hypokalemia or hypomagnesemia, and in patients receiving other drugs known to prolong the QT interval.

Somnolence

IGALMI™ can cause somnolence. In placebo-controlled clinical studies in adults with agitation associated with schizophrenia or bipolar I or II disorder, somnolence (including fatigue and sluggishness) was reported in 23% and 22% of patients treated with IGALMI™ 180 mcg and 120 mcg, respectively, compared to 6% of placebo-treated patients. Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or operating hazardous machinery, for at least eight hours after taking IGALMI™.

Risk of Withdrawal Reactions

Symptoms of withdrawal have been observed after procedural sedation with another dexmedetomidine product administered intravenously. In this study, 12 (5%) adult patients who received intravenous dexmedetomidine up to 7 days (regardless of dose) experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing dexmedetomidine and 7 (3%) adult patients who received intravenous dexmedetomidine experienced at least 1 event related with withdrawal 24 to 48 hours after discontinuing dexmedetomidine. The most common withdrawal reactions were nausea, vomiting, and agitation. In these subjects, tachycardia and hypertension requiring intervention occurred at a frequency of <5% in the 48 hours following intravenous dexmedetomidine discontinuation.

IGALMI™ was not studied for longer than 24 hours after the first dose. There may be a risk of physical dependence and a withdrawal syndrome if IGALMI™ is used in a manner other than indicated.

Tolerance and Tachyphylaxis

Use of another dexmedetomidine product administered intravenously beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions.

IGALMI™ was not studied for longer than 24 hours after the first dose. There may be a risk of tolerance and tachyphylaxis if IGALMI™ is used in a manner other than indicated).

Adverse Reactions

The following adverse reactions are discussed in detail in other sections of the labeling:

Hypotension, Orthostatic Hypotension, and Bradycardia, QT Interval Prolongation, Somnolence, Risk of Withdrawal Reactions and Tolerance and Tachyphylaxis

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

The safety of IGALMI™ was evaluated in 507 adult patients with agitation associated with schizophrenia (N=255) or bipolar I or II disorder (N=252) in two randomized, placebo-controlled studies (Studies 1 and 2) In both studies, patients were admitted to a clinical research unit or a hospital and remained under medical supervision for at least 24 hours following treatment. Patients were 18 to 71 years of age (mean age was 46 years old); 45% were female and 55% were male; 66% were Black, 31% were White, 2% were multiracial, and 1% were other.

In these studies, patients received an initial dose of IGALMI™ 180 mcg (N=252), IGALMI™ 120 mcg (N=255), or placebo (N=252). Patients who were hemodynamically stable (i.e., those with systolic blood pressure (SBP) >90 mmHg, diastolic blood pressure (DBP) >60 mmHg, and heart rate (HR) >60 beats per minute) and without orthostatic hypotension (i.e., reduction in SBP <20 mmHg or DBP <10 mmHg upon standing) were eligible for an additional dose after 2 hours. An additional half dose (90 mcg, 60 mcg, or placebo) was given to 7.1% (18/252), 22.7% (58/255) and 44.0% (111/252) of patients in the IGALMI™ 180 mcg, IGALMI™ 120 mcg or placebo arms, respectively. After at least an additional 2 hours, an additional second half dose (total IGALMI™ dose of 360 mcg, total IGALMI™ dose of 240 mcg, or placebo, respectively) was given to 3.2% (8/252), 9.4% (24/255), and 21.0% (53/252) of patients in the IGALMI™ 180 mcg, IGALMI™ 120 mcg or placebo arms, respectively.

In these studies, one patient discontinued treatment due to an adverse reaction of oropharyngeal pain.

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were: somnolence, oral paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension.

Table 50 presents the adverse reactions that occurred in IGALMI™-treated patients at a rate of at least 2% and at a higher rate than in placebo-treated patients in Studies 1 and 2.

TABLE 50 Adverse Reactions Reported in ≥2% of IGALMI ™-Treated Patients and Greater than Placebo in Two Placebo-Controlled Studies of Agitated Adult Patients with Schizophrenia or Bipolar I or II Disorder (Studies 1 and 2) IGALMI ™ IGALMI ™ 180 mcg 120 mcg Placebo (N = 252) (N = 255) N = 252 Adverse Reaction % % % Somnolence* 23 22 6 Paresthesia oral or 7 6 1 hypoesthesia oral Dizziness 6 4 1 Hypotension 5 5 0 Orthostatic hypotension 5 3 <1 Dry mouth 4 7 1 Nausea 3 2 2 Bradycardia 2 2 0 Abdominal discomfort† 2 0 1 *Somnolence includes the terms fatigue and sluggishness †Abdominal discomfort includes dyspepsia, gastroesophageal reflux disease

Hypotension, Orthostatic Hypotension, and Bradycardia in Two Placebo-Controlled Studies

In clinical studies, patients were excluded if they were treated with alpha-1 noradrenergic blockers, benzodiazepines, antipsychotic drugs, or other hypnotics four hours prior to study drug administration; had a history of syncope or syncopal attacks; their SBP was less than 110 mmHg; their DBP was less than 70 mmHg; their HR was less than 55 beats per minute; or they had evidence of hypovolemia or orthostatic hypotension. In these studies, vital signs were monitored (at 30 minutes, 1-, 2-, 4-, 6-, and 8-hours post-dose), including orthostatic vital signs at 2-, 4-, and 8-hours post-dose. Maximum positional decreases in SBP and DBP after standing were observed at two hours post-dose. Maximal reductions on BP and HR were observed two hours post-dose. Table 51 presents the mean BP and HR decrease across all patients from both studies at 2 hours post dose.

TABLE 51 Mean Blood Pressure and Heart Rate Decrease at 2 Hours Post-Dose IGALMI ™ IGALMI ™ 180 mcg 120 mcg Placebo (N = 252) (N = 255) (N = 252) Mean SBP Decrease (mmHg) 15 13 1 Mean DBP Decrease (mmHg) 8 7 <1 Mean Heart Rate Decrease 9 7 3 (bpm)

In the Clinical Studies:

(a) 13%, 8%, and <1% of patients in the single dose 180 mcg IGALMI™, 120 mcg IGALMI™, and placebo groups, respectively, experienced SBP ≤90 mmHg and a decrease ≥20 mmHg of SBP within 24 hours of dosing.

(b) 19%, 17%, and 2% of the patients in the 180 mcg IGALMI™, 120 mcg IGALMI™, and placebo groups, respectively, had a DBP ≤60 mmHg and a DBP decrease ≥10 mmHg within 24 hours of dosing.

(c) 4%, 3%, and 0% of patients in the 180 mcg IGALMI™, 120 mcg IGALMI™, and placebo groups, respectively, had a HR ≤50 beats per minute and a HR decrease ≥20 beats per minute within 24 hours of dosing.

At 8 hours post-dose, 2% of patients in the IGALMI™ 180 mcg group experienced a SBP ≤90 mmHg and decrease ≥20 mmHg compared with one patient (<1%) in the IGALMI™ 120 mcg group and none in the placebo group. At 24 hours, none of the patients in the IGALMI™ 180 mcg group experienced a SBP ≤90 mmHg and decrease ≥20 mmHg compared with one patient (<1%) in the IGALMI™ 120 mcg group and none in the placebo group. At 8 hours post-dose, none of the patients in the IGALMI™ 180 mcg group had a HR ≤50 beats per minute and a HR decrease ≥20 beats per minute compared with one patient in the 120 mcg group (<1%) and none in the placebo group.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of another dexmedetomidine product given intravenously (IGALMI™ is not approved for intravenous use). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Anemia

Cardiac Disorders: Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia

Eye Disorders: Photopsia, visual impairment

Gastrointestinal Disorders: Abdominal pain, diarrhea, nausea, vomiting

General Disorders and Administration Site Conditions: Chills, hyperpyrexia, pain, pyrexia, thirst

Hepatobiliary Disorders: Hepatic function abnormal, hyperbilirubinemia

Investigations: Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolonged

Metabolism and Nutrition Disorders: Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia

Nervous System Disorders: Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder

Psychiatric Disorders: Agitation, confusional state, delirium, hallucination, illusion

Renal and Urinary Disorders: Oliguria, polyuria

Respiratory, Thoracic and Mediastinal Disorders: Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis

Skin and Subcutaneous Tissue Disorders: Hyperhidrosis, pruritus, rash, urticaria

Surgical and Medical Procedures: Light anesthesia

Vascular Disorders: Blood pressure fluctuation, hemorrhage, hypertension, hypotension

Drug Interactions

Drugs that Prolong the QT Interval

Concomitant use of drugs that prolong the QT interval may add to the QT-prolonging effects of IGALMI™ and increase the risk of cardiac arrhythmia. Avoid the use of IGALMI™ in combination with other drugs known to prolong the QT interval.

Anesthetics, Sedatives, Hypnotics, and Opioids

Concomitant use of IGALMI™ with anesthetics, sedatives, hypnotics, or opioids is likely to lead to enhanced CNS depressant effects. Specific studies with another dexmedetomidine product given intravenously have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. Due to possible enhanced CNS effects when given concomitantly with IGALMI, consider a reduction in dosage of IGALMI™ or the concomitant anesthetic, sedative, hypnotic, or opioid.

Use in Specific Populations

Pregnancy

Risk Summary

There are no available data on IGALMI™ use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal effects. Available data from published randomized controlled trials and case reports over several decades of use with intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of major birth defects or miscarriage; however, the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of cesarean-section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores. Available data indicate that dexmedetomidine crosses the placenta.

In animal reproductive studies fetal toxicity occurred in the presence of maternal toxicity with subcutaneous administration of dexmedetomidine to pregnant rats during organogenesis at doses 5 times the maximum recommended human dose [MRHD] of 360 mcg/day based on mg/m2 body surface area. Adverse developmental effects, including early implantation loss and decreased viability of second generation offspring, occurred when pregnant rats were subcutaneously administered doses less than or equal to the MRHD based on mg/m2 from late pregnancy through lactation and weaning.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Increased post-implantation losses and reduced live pups in the presence of maternal toxicity (decreased body weight) occurred in a rat embryo-fetal development study in which pregnant dams were administered subcutaneous doses of dexmedetomidine of 200 mcg/kg/day (equivalent to 5 times the MRHD of 360 mcg/day based on mg/m2) during the period of organogenesis (Gestation Day (GD) 5 to 16). No embryo-fetal toxicity was observed at 20 mcg/kg/day (less than the MRHD of 360 mcg/day based on mg/m2). No malformations were reported at any dose level.

No malformation or embryo-fetal toxicity were observed in a rabbit embryo-fetal developmental study in which pregnant dams were administered dexmedetomidine intravenously at doses up to 96 mcg/kg/day (equivalent to 5 times the MRHD of 360 mcg/day based on mg/m2) during the period of organogenesis (GD 6 to 18).

Reduced pup and adult offspring weights and grip strength were reported in a rat developmental toxicology study in which pregnant females were administered dexmedetomidine subcutaneously at 8 mcg/kg/day (less than the MRHD of 360 mcg/day based on mg/m2) during late pregnancy through lactation and weaning (GD 16 to postnatal day [PND] 25). Decreased viability of second generation offspring and an increase in early implantation loss along with delayed motor development occurred at 32 mcg/kg/day (equivalent to the MRHD of 360 mcg/day based on mg/m2) when first generation offspring were mated. This study limited dosing to hard palate closure (GD 15-18) through weaning instead of standard dosing from implantation (GD 6-7) to weaning (PND 21).

Lactation

Risk Summary

Available published literature report the presence of dexmedetomidine in human milk following intravenous administration. There is no information regarding the effects of dexmedetomidine on the breastfed child or the effects on milk production. Advise women to monitor the breastfed infant for irritability. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for IGALMI™ and any potential adverse effects on the breastfed child from IGALMI™ or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of IGALMI™ have not been established in pediatric patients.

Geriatric Use

Fifteen geriatric patients (≥65 years of age) were enrolled (no patients were 75 years of age and older) in the clinical studies for acute treatment of agitation associated with schizophrenia or bipolar I or II disorder. Of the total number of IGALMI™-treated patients in these clinical studies, 11/507 (2.2%) were 65 years of age and older.

Dosage reduction of IGALMI™ is recommended in geriatric patients. A higher incidence of bradycardia and hypotension was observed in geriatric patients compared to younger adult patients after intravenous administration of another dexmedetomidine product. The pharmacokinetic profile of intravenous dexmedetomidine was not altered in geriatric subjects.

Hepatic Impairment

Dexmedetomidine clearance was decreased in patients with hepatic impairment (Child-Pugh Class A, B, or C). Thus, a dosage reduction of IGALMI™ is recommended in patients with hepatic impairment compared to patients with normal hepatic function.

Drug Abuse and Dependence

Controlled Substance

IGALMI™ contains dexmedetomidine, which is not a controlled substance.

Dependence

Physical Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. The dependence potential of dexmedetomidine has not been studied in humans. However, because studies in rodents and primates have demonstrated that intravenous dexmedetomidine exhibits pharmacologic actions similar to those of clonidine, it is possible that dexmedetomidine may produce a clonidine-like withdrawal syndrome upon abrupt discontinuation.

IGALMI™ was not studied for longer than 24 hours after the first dose. There may be risk of physical dependence and a withdrawal syndrome if IGALMI™ is used in a manner other than indicated.

Tolerance

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

IGALMI™ has not been studied for longer than 24 hours after the first dose. There may be a risk for tolerance if IGALMI™ is administered in a manner other than indicated.

Overdosage

In a tolerability study of intravenous dexmedetomidine in which healthy adult subjects were administered doses at and above the recommended dose of 0.2 to 0.7 mcg/kg/hour, the maximum blood concentration was approximately 13 times the upper boundary of the therapeutic range for the intravenous dexmedetomidine (IGALMI™ is not approved for intravenous use). The most notable effects observed in two subjects who achieved the highest doses were first degree atrioventricular block and second-degree heart block.

Five adult patients received an overdose of intravenous dexmedetomidine in intensive care unit sedation studies. Two patients who received a 2 mcg/kg loading dose (twice the recommended loading dose) over 10 minutes, experienced bradycardia and/or hypotension.

One patient who received a loading intravenous bolus dose of undiluted dexmedetomidine (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.

Description

IGALMI™ contains dexmedetomidine, an alpha-2 adrenergic receptor agonist, present as dexmedetomidine hydrochloride, the S-enantiomer of medetomidine chemically described as 4-[(1S)-1-(2, 3-dimethylphenyl) ethyl]-1H-imidazole hydrochloride. The empirical formula is C13H16N2·HCl with a molecular weight of 236.7 g/mol. The structural formula of dexmedetomidine hydrochloride is:

Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in water and has a pKa of 7.1. Its partition coefficient in octanol/water at pH 7.4 is 2.89.

IGALMI™ is for sublingual or buccal use. Each IGALMI™ sublingual film contains 120 mcg or 180 mcg of dexmedetomidine equivalent to 141.8 mcg and 212.7 mcg of dexmedetomidine hydrochloride, respectively.

IGALMI™ contains the following inactive ingredients: FD&C Blue #1 colorant, hydroxypropyl cellulose, peppermint oil, polyethylene oxide, and sucralose.

Clinical Pharmacology

Mechanism of Action

Dexmedetomidine is an alpha-2 adrenergic receptor agonist. The mechanism of action of IGALMI in the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder is thought to be due to activation of presynaptic alpha-2 adrenergic receptors.

Pharmacodynamics

Dexmedetomidine acts as an agonist at alpha-2 adrenergic receptors with binding affinities (Ki values) of 4 to 6 nM at the alpha-2 adrenergic receptor subtypes.

Cardiac Electrophysiology

IGALMI™ exhibits a concentration dependent QT prolongation. Table 52 shows the mean (upper 90% confidence interval) QTcF increase from baseline for respective dosing regimens.

TABLE 52 QTcF Increase from Baseline by Dosage of IGALMI ™ Mean QTcF Increase from Baseline (upper IGALMI ™ Dosage 90% confidence interval) 120 mcg single use 6 (7) msec 120 mcg + 2 additional doses of 8 (9) msec 60 mcg 2 hours apart (total 3 doses) 180 mcg single use 8 (11) msec 180 mcg + 2 additional doses of 11 (14) msec 90 mcg 2 hours apart (total 3 doses)

Pharmacokinetics

Dexmedetomidine exposure (Cmax and AUC) increased in a dose proportional manner in the dose range of 20 mcg (0.17 times the lowest recommended initial dose of 120 mcg) to 180 mcg after single sublingual administration of IGALMI™.

The mean time for film to dissolve in the mouth was about 6 to 8 minutes and 18 minutes following sublingual and buccal administration, respectively. Dexmedetomidine was quantifiable in plasma generally after 5 to 20 minutes post dosing.

Absorption

The absolute bioavailability of dexmedetomidine was about 72% and 82% following sublingual and buccal administration of IGALMI™, respectively. When water was taken at two hours post dose, comparable exposures of dexmedetomidine were observed when IGALMI™ was administered by both routes.

Mean maximal plasma concentrations of dexmedetomidine were reached approximately two hours after sublingual or buccal administration of IGALMI™. Following sublingual administration of 40 mcg of IGALMI™ (0.33 times the lowest recommended initial dose) with water drinking at two hours post dose and 20 mcg dexmedetomidine intravenous infusion for 90 minutes in healthy volunteers. The mean peak plasma concentration (Cmax) of dexmedetomidine was 143 ng/L and 144 ng/L, respectively. The mean area under concentration curve (AUC) of dexmedetomidine was 851 hour*ng/L and 584 hour*ng/L, respectively.

Effect of Drinking Water on Absorption

Compared to drinking water at two hours post sublingual administration of IGALMI, early water intake (as early as 15 minutes post dose) had minimal effects on the rate or extent of absorption of dexmedetomidine.

Effects of early water intake (i.e., before two hours post dose) on the absorption of dexmedetomidine has not been evaluated following buccal administration.

Distribution

The steady-state volume of distribution (Vss) of dexmedetomidine following intravenous administration was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of dexmedetomidine that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects.

The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro, and negligible changes in the plasma protein binding of dexmedetomidine IV were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by dexmedetomidine hydrochloride injection was explored in vitro and none of these compounds appeared to be significantly displaced by intravenous dexmedetomidine.

Elimination

Metabolism

Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6 with a minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomi dine, and 3-carboxy-dexmedetomidine; and N-methylation of dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl 0-glucuronide.

Excretion

The mean terminal elimination half-life (t_(1/2)) of dexmedetomidine is approximately 2.8 hours following sublingual or buccal administration of IGALMI™. Clearance is estimated to be approximately 39 L/h following intravenous administration.

A mass balance study demonstrated that after nine days, an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N-methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified.

Specific Populations

Male and Female Patients

There was no observed difference in the pharmacokinetics of intravenous dexmedetomidine due to sex.

Geriatric Patients

The pharmacokinetic profile of intravenous dexmedetomidine was not altered by age. There were no differences in the pharmacokinetics of intravenous dexmedetomidine in young (18-40 years), middle age (41-65 years), and geriatric (>65 years) subjects.

Patients with Hepatic Impairment

In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for intravenous dexmedetomidine were lower than in subjects with normal hepatic function [see Dosage and Administration (2.2)]. After an intravenous infusion of 0.6 mcg/kg of this dexmedetomidine product over 10 minutes the mean clearance values for subjects with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in subjects with normal hepatic function, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in subjects with normal hepatic function, respectively.

Patients with Renal Impairment

Dexmedetomidine pharmacokinetics (Cmax, Tmax, AUC, t1/2, CL, and V) were not significantly different in patients with creatinine clearance <30 mL/minute compared to subjects with normal renal function.

Drug Interactions Studies

In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Animal carcinogenicity studies have not been performed with dexmedetomidine.

Mutagenesis

Dexmedetomidine was not mutagenic in the in vitro Ames bacterial reverse mutation test or mammalian mouse lymphoma cell forward mutation assay. Dexmedetomidine was not clastogenic in the in vitro human lymphocyte chromosome aberration test in the absence or presence of human liver S9 metabolic activation, however, a weak clastogenic response was noted in the presence of rat liver S9 metabolic activation. Dexmedetomidine was not clastogenic in the in vivo bone marrow micronucleus test in CD-1 mice, although there was some evidence for clastogenicity in NMRI mice.

Impairment of Fertility

Fertility in male or female rats was not affected after daily subcutaneous injections of dexmedetomidine at doses up to 54 mcg/kg (1.5 times the MRHD of 360 mcg/day on a mg/m2 basis) administered from 10 weeks prior to mating in males, and 3 weeks prior to mating and during mating in females.

Animal Toxicology and/or Pharmacology

Twice daily sublingual administration of 120 to 320 mcg/day of dexmedetomidine to dogs for 28 days caused decreased heart rate and moderate sedation up to 3.5 hours post dose. A single male dog (out of 32 treated dogs) dosed 320 mcg/day (equivalent to the MRHD of 360 mcg/day) exhibited inflammation, necrosis, myofiber degeneration, and hemorrhage at the sublingual treatment site. No adverse effects were noted at 240 mcg/day (less than the MRHD of 360 mcg/day).

Clinical Studies

The effectiveness of IGALMI™ for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults was established in two randomized, double-blind, placebo-controlled, fixed-dose studies (Studies 1 and 2):

Study 1 (NCT04268303) included 380 patients who met DSM-5 criteria for schizophrenia, schizoaffective or schizophreniform disorder. The population was 18 to 71 years of age (mean age was 46 years old); 37% female and 63% male; 78% Black, 20% White, 1% multiracial, and 1% Asian.

Study 2 (NCT04276883) included 378 patients who met DSM-5 criteria for bipolar I or II disorder. The population was 18 to 70 years of age (mean age was 47 years old); 55% female and 45% male; 56% Black, 41% White, 1% Asian, 1% multiracial, and 1% other.

The Positive and Negative Syndrome Scale-Excited Component (PEC) is an investigator-rated instrument consisting of 5 items: poor impulse control, tension, hostility, uncooperativeness, and excitement. Each item is scored on a scale from 1 to 7 (1=absent, 2=minimal, 3=mild, 4=moderate, 5=moderate-severe, 6=severe, 7=extremely severe). The total PEC score ranges from 5 to 35, with higher scores reflecting greater overall symptom severity. For enrollment in the studies, patients had to be judged to be clinically agitated with a total PEC score of ≥14, with at least one individual item score ≥4. In both studies, patients were admitted to a clinical research unit or a hospital and remained under medical supervision for at least 24 hours following treatment.

Patients were randomized to receive a single sublingual dose of 180 mcg of IGALMI™, 120 mcg of IGALMI™, or placebo. The primary efficacy endpoint in both studies was the change from baseline in the PEC score, assessed two hours following the initial dose. The key secondary endpoint was the time to effect onset, assessed by measuring the change from baseline in PEC score at 10, 20, 30, 45, 60, and 90 minutes after the initial dose administration.

In both studies, mean baseline PEC scores were similar in all treatment groups (Table 53). The mean change from baseline in the PEC total score at two hours after the first dose in patients treated with 180 mcg and 120 mcg of IGALMI™ was statistically greater than patients who received placebo (Table 53).

Examination of population subsets (race and sex) on the primary endpoint did not show evidence for differential responsiveness between White and Black or female and male patients. The clinical studies did not include enough patients of other races or patients ≥65 years of age to determine whether there were differences in effectiveness for those groups.

TABLE 53 Primary Efficacy Results for Change from Baseline in the PEC Score at Two Hours in Agitated Patients with Schizophrenia or Bipolar I or II Disorder (Studies 1 and 2) LS Mean Mean Change from Baseline Baseline to Number PEC 2 hour Post LS Mean Treatment of Score First Dose Difference Study Group Patients (SD) (SE) (95% CI) Study IGALMI ™ 125 17.6 (2.7) −10.3 (0.4) −5.5 1 180 mcg* (−6.5, −4.4) IGALMI ™ 129 17.5 (2.5)  −8.5 (0.4) −3.7 120 mcg* (−4.8, −2.7) Placebo 126 17.6 (2.3)  −4.8 (0.4) — Study IGALMI ™ 126 18.0 (3.0) −10.4 (0.4) −5.4 2 180 mcg* (−6.5, −4.3) IGALMI ™ 126 18.0 (2.7)  −9.1 (0.4) −4.1 120 mcg* (−5.1, −3.0) Placebo 126 17.9 (2.9)  −5.0 (0.4) — SD = standard deviation; SE = standard error; LS Mean = least-squares mean; CI = unadjusted confidence interval; PEC = Positive and Negative Syndrome Scale-Excited Component *IGALMI ™ doses that were statistically significantly superior to placebo after adjusting for multiplicity.

How Supplied/Storage and Handling

How Supplied

IGALMI (dexmedetomidine) sublingual film is supplied as a blue rectangular sublingual film, containing on its surface two darker blue spots in dose strengths of 120 mcg and 180 mcg and is packaged as individual films in heat-sealed foil pouches in 10-count and 30-count films per carton. The NDC number for each packaging configuration is: 120 mcg 10-count NDC #81092-1120-1, 120 mcg 30-count NDC #81092-1120-3, 180 mcg 10-count NDC #81092-1180-1, 180 mcg 30-count NDC #81092-1180-3

Storage and Handling

Store at controlled room temperature, 20° C. to 25° C. (68° F. to 77° F.). Excursions permitted from 15° C. to 30° C. (59° F. to 86° F.). See USP Controlled Room Temperature.

Keep IGALMI in the foil pouch until ready to administer.

Patient Counseling Information

Administration Information

Advise patients to place IGALMI™ under the tongue, close to the base of the tongue, on the left or right side (sublingual) or behind the lower lip (buccal).

Advise patients not to chew or swallow IGALMI™. Also, advise patients not to eat or drink for at least 15 minutes after sublingual administration, or at least 1 hour after buccal administration.

Hypotension, Orthostatic Hypotension, and Bradycardia

Advise patients that IGALMI™ can cause dose-dependent hypotension, orthostatic hypotension, and bradycardia. Inform patients to remain sitting or lying down after receiving IGALMI™ and to inform the healthcare provider if they have any symptoms of hypotension or bradycardia.

QT Interval Prolongation

Inform patients to consult their physician immediately if they feel faint or have heart palpitations.

Somnolence

Advise patients that IGALMI™ can cause somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Advise patients that they should avoid doing activities that require them to be alert, such as driving a car or operating machinery for at least eight hours after receiving IGALMI™.

Lactation

Advise patients exposed to IGALMI™ to monitor breastfed infants for irritability.

It is to be appreciated that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections may set forth one or more but not all exemplary embodiments of the present invention as contemplated by the inventor(s), and thus, are not intended to limit the present invention and the appended claims in any way.

The present disclosure has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.

The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

The claims in the instant application are different than those of the parent application or other related applications. The Applicant therefore rescinds any disclaimer of claim scope made in the parent application or any predecessor application in relation to the instant application. The Examiner is therefore advised that any such previous disclaimer and the cited references that it was made to avoid, may need to be revisited. Further, the Examiner is also reminded that any disclaimer made in the instant application should not be read into or against the parent application.

All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world. 

What is claimed is:
 1. A method of treating agitation associated with schizophrenia or bipolar I or II disorder in a human subject comprising: administering an initial dose of dexmedetomidine or a pharmaceutically acceptable salt thereof in an oromucosal formulation to the human; administering a second dose of dexmedetomidine or the pharmaceutically acceptable salt thereof in the oromucosal formulation to the human subject at least two hours after and within 24 hours of the initial dose; and administering a third dose of dexmedetomidine or the pharmaceutically acceptable salt thereof in the oromucosal formulation to the human subject at least two hours after the second dose and within 24 hours of the initial dose; wherein the administration of the dexmedetomidine does not exceed a maximum total daily dosage; wherein the human subject has a severe hepatic impairment and the agitation is severe; and wherein the initial dose is 90 mcg of dexmedetomidine, the second and third doses are each 60 mcg of dexmedetomidine, and the maximum total daily dosage is 210 mcg of dexmedetomidine.
 2. The method of claim 1, wherein the agitation is severe as defined by a PEC score of 20 or higher and the hepatic impairment is severe as defined by Child-Pugh Class C.
 3. The method of claim 1, wherein the oromucosal formulation further comprises at least one water-soluble polymer.
 4. The method of claim 3, wherein the at least one water-soluble polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxy methylcellulose, methylcellulose, polyethylene oxide (PEO), and mixtures thereof.
 5. The method of claim 4, wherein the at least one water-soluble polymer is hydroxypropyl cellulose. 